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{\*\bkmkstart filing_1}{\*\bkmkend filing_1}{\*\bkmkstart doc_1_1}{\*\bkmkend doc_1_1}\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs4\ql \~\par\pard\plain\cf1\f51\fs34\b\qc UNITED STATES SECURITIES AND EXCHANGE COMMISSION\par\pard\plain\cf1\f51\fs18\b\qc Washington,\~D.C. 20549\par\pard\plain\cf1\f51\fs10\qc \~\par\pard\plain\cf1\f51\fs34\b\qc Form\~10-K\par\pard\plain\cf1\f51\fs12\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f54\fs18\ql þ\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\b\ql ANNUAL REPORT PURSUANT TO SECTION\~13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\cell{
{\trowd\clvertalc\cellx360\cellx740\clvertalc\cellx800\cellx10323\trrh225\row}}}\pard\plain\li924\fi-660\cf1\f51\fs10\ql \~\par\pard\plain\fi792\cf1\f51\fs18\b\ql For the Fiscal Year Ended December\~31, 2017\par\pard\plain\li924\cf1\f51\fs10\ql \~\par\pard\plain\cf1\f51\fs18\b\qc OR\par\pard\plain\cf1\f51\fs10\qc \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f54\fs18\b\ql ¨\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\b\ql TRANSITION REPORT PURSUANT TO SECTION\~13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\plain\intbl\cf1\f51\fs18\b\ql \~\~\~\~\~\~\~\~\~\~\~\~\cell{
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\par\pard\plain\cf1\f51\fs10\qc \~\par\pard\plain\cf1\f51\fs40\b\qc IDERA PHARMACEUTICALS, INC.\par\pard\plain\cf1\f51\fs14\b\qc (Exact name of Registrant as specified in its charter)\par\pard\plain\cf1\f51\fs10\qc \~
\par\pard\plain
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh66
\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
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{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh223
\pard\plain\intbl\cf1\f51\fs18\b\qc Delaware\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 04-3072298\cell{
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh223\row}}}
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh173
\pard\plain\intbl\cf1\f51\fs14\b\qc (State or other jurisdiction\cell\pard\plain\intbl\cf1\f51\fs14\b\qc (I.R.S. Employer\cell{
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh173\row}}}
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh173
\pard\plain\intbl\cf1\f51\fs14\b\qc of incorporation or organization)\cell\pard\plain\intbl\cf1\f51\fs14\b\qc Identification No.)\cell{
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh173\row}}}
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh99
\pard\plain\intbl\cf1\f51\fs8\qc \~\cell\pard\plain\intbl\cf1\f51\fs8\qc \~\cell{
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh99\row}}}
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh223
\pard\plain\intbl\cf1\f51\fs18\b\qc 167 Sidney Street\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 02139\cell{
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh223\row}}}
{\trowd\trqc\clvertalb\cellx5161\clvertalb\cellx10323\trrh173
\pard\plain\intbl\cf1\f51\fs14\b\qc Cambridge, Massachusetts\cell\pard\plain\intbl\cf1\f51\fs14\b\qc (Zip Code)\cell{
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\pard\plain\intbl\cf1\f51\fs14\b\qc (Address of principal executive offices)\cell\pard\plain\intbl\cf1\f51\fs14\qc \~\cell{
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\pard\plain\intbl\cf1\f51\fs14\b\qc Title of Class:\cell\pard\plain\intbl\cf1\f51\fs14\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs14\b\qc Name of Each Exchange on Which Registered\cell{
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\pard\plain\intbl\cf1\f51\fs18\b\qc Common Stock, $.001\~par value\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc Nasdaq Capital Market\cell{
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\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs18\ql Large accelerated filer\~\~\u9744?\cell\pard\plain\intbl\cf1\f51\fs18\ql Accelerated filer\~\~\u9745?\cell\pard\plain\intbl\cf1\f51\fs18\ql Non-accelerated filer\~\~\u9744? \~ \~(Do not check if a smaller\plain\intbl\cf1\f51\fs18\ql reporting company)\cell{
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\pard\plain\intbl\cf1\f51\fs18\ql Smaller\~reporting\~company\~\~\u9744?\cell\pard\plain\intbl\cf1\f51\fs18\ql Emerging growth\~company\~\~\u9744?\cell\pard\plain\intbl\cf1\f51\fs18\qc \~\cell{
{\trowd\trqc\cellx2580\cellx7741\cellx10323\trrh223\row}}}\pard\plain\cf1\f51\fs8\ql \~{\*\bkmkstart _cp_text_1_4_12112272}{\*\bkmkend _cp_text_1_4_12112272}\par\pard\plain\fi396\cf1\f51\fs18\ql If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for\plain\cf1\f51\fs18\ql complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.\u9744?\par\pard\plain\cf1\f51\fs8\ql \~\par\pard\plain\fi396\cf1\f51\fs18\ql Indicate by check mark whether the registrant is a shell company (as defined in Rule\~12b-2 of the Exchange\plain\cf1\f51\fs18\ql Act.)\~\~\~\~Yes\~\~\u9744?\~\~\~\~No\~\~ \u9745?\~\par\pard\plain\cf1\f51\fs8\ql \~\par\pard\plain\fi396\cf1\f51\fs18\ql The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant was $203,037,675\plain\cf1\f51\fs18\ql based on the last sale price of the registrant\u8217?s common stock as reported on the Nasdaq Capital Market on June\~30, 2017 (the last\plain\cf1\f51\fs18\ql business day of the registrant\u8217?s most recently completed second fiscal quarter).\par\pard\plain\fi396\cf1\f51\fs8\ql \~\par\pard\plain\fi396\cf1\f51\fs18\ql As of February 15, 2018, the registrant had 195,635,196\~shares of common stock outstanding.\par\pard\plain\brdrb\brdrs\fi396\cf1\f51\fs4\ql \~\par\pard\plain\cf1\f51\fs4\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li88\ri88\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs24\b\qc IDERA PHARMACEUTICALS, INC.\par\pard\plain\cf1\f51\fs24\b\qc FORM\~10-K\par\pard\plain\cf1\f51\fs24\qc \~{\*\bkmkstart toc_12112272}{\*\bkmkend toc_12112272}\par\pard\plain\cf11\f51\fs24\b\qc TABLE OF CONTENTS\par\pard\plain\cf1\f51\fs20\qc \~
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{\trowd\cellx782\cellx9002\cellx9688\trrh495\row}}}\pard\plain\fi528\cf1\f51\fs20\qc __________________________________\par\pard\plain\fi528\cf1\f51\fs20\qc \~\par\pard\plain\fi594\cf1\f51\fs20\ql IMO\plain\cf1\f51\fs10\ql \u174?\plain\cf1\f51\fs20\ql and Idera\plain\cf1\f51\fs10\ql \u174?\plain\cf1\f51\fs20\ql are our trademarks. All other trademarks and service marks appearing in this Annual\plain\cf1\f51\fs20\ql Report on Form\~10-K are the property of their respective owners.\par\pard\plain\sb528\cf1\f51\fs20\qc i\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\qc NOTE REGARDING FORWARD-LOOKING STATEMENTS\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\fi594\cf1\f51\fs20\ql This Annual Report on Form 10-K (this Form 10-K) and the documents we incorporate by reference contain\plain\cf1\f51\fs20\ql forward-looking statements within the meaning of Section\~27A of the Securities Act of 1933, as amended, and\plain\cf1\f51\fs20\ql Section\~21E of the Securities Exchange Act of 1934, as amended,{\*\bkmkstart _cp_text_1_16_12112272}{\*\bkmkend _cp_text_1_16_12112272}\plain\cf1\f51\fs20\ql or the Exchange Act. All statements, other than\plain\cf1\f51\fs20\ql statements of historical fact, included or incorporated in this report regarding our strategy, future operations,\plain\cf1\f51\fs20\ql collaborations, intellectual property, cash resources, financial position, future revenues, projected costs, prospects,\plain\cf1\f51\fs20\ql plans, and objectives of management are forward-looking statements. The words \u8220?believes,\u8221?\plain\cf1\f51\fs20\ql \u8220?anticipates,\u8221? \u8220?estimates,\u8221? \u8220?plans,\u8221? \u8220?expects,\u8221?\plain\cf1\f51\fs20\ql \u8220?intends,\u8221? \u8220?may,\u8221? \u8220?could,\u8221? \u8220?should,\u8221? \u8220?potential,\u8221?\plain\cf1\f51\fs20\ql \u8220?likely,\u8221? \u8220?projects,\u8221? \u8220?continue,\u8221? \u8220?will,\u8221? \u8220?would\u8221?\plain\cf1\f51\fs20\ql and similar expressions are intended to identify forward-looking statements, although not all forward-looking\plain\cf1\f51\fs20\ql statements contain these identifying words. We cannot guarantee that we actually will achieve the plans, intentions\plain\cf1\f51\fs20\ql or expectations disclosed in our forward-looking statements and you should not place undue reliance on our\plain\cf1\f51\fs20\ql forward-looking statements.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql There are a number of important factors that could cause our actual results to differ materially from those\plain\cf1\f51\fs20\ql indicated or implied by forward-looking statements. These important factors include those set forth below under\plain\cf1\f51\fs20\ql Part I, Item\~1A \u8220?Risk Factors.\u8221? These factors and the other cautionary statements made in this Annual\plain\cf1\f51\fs20\ql Report on Form 10-K and the documents we incorporate by reference should be read as being applicable to all\plain\cf1\f51\fs20\ql related forward-looking statements whenever they appear in this Annual Report on Form 10-K and the documents\plain\cf1\f51\fs20\ql we incorporate by reference.{\*\bkmkstart _cp_text_1_18_12112272}{\*\bkmkend _cp_text_1_18_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_19_12112272}{\*\bkmkend _cp_text_1_19_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql This Annual Report on{\*\bkmkstart _cp_text_4_20_12112272}{\*\bkmkend _cp_text_4_20_12112272}\plain\cf1\f51\fs20\ql Form 10-K{\*\bkmkstart _cp_text_1_21_12112272}{\*\bkmkend _cp_text_1_21_12112272}\plain\cf1\f51\fs20\ql also contains statements about our proposed strategic combination with\plain\cf1\f51\fs20\ql BioCryst Pharmaceuticals, Inc.\~\~Many risks and uncertainties could cause actual results to differ materially from\plain\cf1\f51\fs20\ql these forward-looking statements with respect to the pending transaction, and these risks, as well as other risks\plain\cf1\f51\fs20\ql associated with the pending transaction, are more fully disclosed in the joint proxy statement/prospectus that is\plain\cf1\f51\fs20\ql included in the registration statement on Form S-4 (File No. 333-223255) that was filed by Nautilus Holdco, Inc.\plain\cf1\f51\fs20\ql with the{\*\bkmkstart _cp_text_4_22_12112272}{\*\bkmkend _cp_text_4_22_12112272}\plain\cf1\f51\fs20\ql U.S. Securities and Exchange Commission{\*\bkmkstart _cp_text_1_23_12112272}{\*\bkmkend _cp_text_1_23_12112272}\plain\cf1\f51\fs20\ql in connection with the pending merger.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, any forward-looking statements{\*\bkmkstart _cp_text_1_24_12112272}{\*\bkmkend _cp_text_1_24_12112272}\plain\cf1\f51\fs20\ql , including any statements about the proposed transaction,\plain\cf1\f51\fs20\ql represent our estimates only as of the date that this Annual Report on Form 10-K is filed with the Securities and\plain\cf1\f51\fs20\ql Exchange Commission and should not be relied upon as representing our estimates as of any subsequent date. We\plain\cf1\f51\fs20\ql do not assume any obligation to update any forward-looking statements. We disclaim any intention or obligation to\plain\cf1\f51\fs20\ql update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc ii\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}{\*\bkmkstart part_1_2_1}{\*\bkmkend part_1_2_1}\par\pard\plain\cf11\f51\fs24\b\qc PART\~I.{\*\bkmkstart parti_807090_12112272}{\*\bkmkend parti_807090_12112272}\par\pard\plain\cf12\f51\fs20\qc \~{\*\bkmkstart item_1_3_1}{\*\bkmkend item_1_3_1}\par\pard\plain\li1078\fi-1078\cf11\f51\fs24\b\ql Item\~1.Business.{\*\bkmkstart item1business_661586_12112272}{\*\bkmkend item1business_661586_12112272}\par\pard\plain\li1078\fi-1078\cf11\f51\fs24\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Overview\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are a clinical-stage biopharmaceutical company focused on the discovery, development and\plain\cf1\f51\fs20\ql commercialization of novel oligonucleotide therapeutics for oncology and rare diseases. We use two distinct\plain\cf1\f51\fs20\ql proprietary drug discovery technology platforms to design and develop drug candidates: our Toll-like receptor, or\plain\cf1\f51\fs20\ql TLR, targeting technology and our nucleic acid chemistry technology (formerly referred to{\*\bkmkstart _cp_text_4_26_12112272}{\*\bkmkend _cp_text_4_26_12112272}\plain\cf1\f51\fs20\ql as our{\*\bkmkstart _cp_text_1_27_12112272}{\*\bkmkend _cp_text_1_27_12112272}\plain\cf1\f51\fs20\ql third generation\plain\cf1\f51\fs20\ql antisense, or 3GA, technology). We developed these platforms based on our scientific expertise and pioneering work\plain\cf1\f51\fs20\ql with synthetic oligonucleotides as therapeutic agents. Using our TLR targeting technology, we design synthetic\plain\cf1\f51\fs20\ql oligonucleotide-based drug candidates to modulate the activity of specific TLRs. In addition, using our nucleic acid\plain\cf1\f51\fs20\ql chemistry technology, we are developing drug candidates to turn off the messenger RNA, or mRNA, associated\plain\cf1\f51\fs20\ql with disease causing genes. We believe our nucleic acid chemistry technology may potentially reduce the\plain\cf1\f51\fs20\ql immunotoxicity and increase the potency of earlier generation antisense and RNA interference, or RNAi,\plain\cf1\f51\fs20\ql technologies.\par\pard\plain\fi528\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our business strategy is focused on the clinical development of drug candidates for oncology and rare\plain\cf1\f51\fs20\ql diseases characterized by small, well-defined patient populations with serious unmet medical needs. We believe we\plain\cf1\f51\fs20\ql can develop and commercialize these targeted therapies on our own. To the extent we seek to develop drug\plain\cf1\f51\fs20\ql candidates for broader disease indications, we have entered into and may explore additional collaborative alliances\plain\cf1\f51\fs20\ql to support development and commercialization.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql TLR Modulation Technology Platform\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql TLRs are key receptors of the immune system and play a role in innate and adaptive immunity. As a result,\plain\cf1\f51\fs20\ql we believe TLRs are potential therapeutic targets for the treatment of a broad range of diseases. Using our\plain\cf1\f51\fs20\ql chemistry-based platform, we have designed TLR agonists and antagonists to act by modulating the activity of\plain\cf1\f51\fs20\ql targeted TLRs. A TLR agonist is a compound that stimulates an immune response through the targeted TLR. A\plain\cf1\f51\fs20\ql TLR antagonist is a compound that inhibits an immune response by blocking the targeted TLR.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our TLR agonist lead drug candidate IMO-2125 is an agonist of TLR9. Our TLR antagonist lead drug\plain\cf1\f51\fs20\ql candidate is IMO-8400, which is an antagonist of TLR7, TLR8 and TLR9.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are developing IMO-2125, via intra-tumoral injection, for the treatment of anti-PD1 refractory\plain\cf1\f51\fs20\ql metastatic melanoma in combination with ipilimumab, an anti-CTLA4 antibody marketed as Yervoy\u174? by\plain\cf1\f51\fs20\ql Bristol-Myers Squibb Company. We are also investigating the combination of intra-tumoral IMO-2125 in\plain\cf1\f51\fs20\ql combination with pembrolizumab for the treatment of anti-PD1 refractory metastatic melanoma and intratumoral\plain\cf1\f51\fs20\ql IMO-2125 in various solid tumors as monotherapy. We are developing IMO-8400 for the treatment of\plain\cf1\f51\fs20\ql dermatomyositis.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Nucleic Acid Chemistry Technology Platform\plain\cf1\f51\fs20\b\ql \~\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are developing our nucleic acid chemistry technology to \u8220?turn off\u8221? the mRNA associated\plain\cf1\f51\fs20\ql with disease causing genes. We have designed gene silencing oligonucleotides to specifically address challenges\plain\cf1\f51\fs20\ql associated with earlier generation antisense and RNAi technologies.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have selected IDRA-008 as our first nucleic acid chemistry research program candidate that we plan to\plain\cf1\f51\fs20\ql enter into clinical development.\~IDRA-008 targets the Apolipoprotein C-III (APOC-III) gene and is being\plain\cf1\f51\fs20\ql developed for the treatment of Familial Chylomicronemia Syndrome (FCS) and Familial Partial Lipodystrophy\plain\cf1\f51\fs20\ql (FPL) which have available pre-clinical animal models and well-known clinical endpoints. We expect our\plain\cf1\f51\fs20\ql development decision to be made based on the totality of IND-enabling studies and our comparator pharmacology\plain\cf1\f51\fs20\ql study with the competitive development asset Volanesorsen.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 1\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf11\f51\fs24\b\ql Agreement and Plan of Merger\par\pard\plain\cf11\f51\fs24\ql \~{\*\bkmkstart _cp_text_1_40_12112272}{\*\bkmkend _cp_text_1_40_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql As further described in Note 17\~to the financial statements appearing elsewhere in this Annual Report on{\*\bkmkstart _cp_text_4_41_12112272}{\*\bkmkend _cp_text_4_41_12112272}\plain\cf1\f51\fs20\ql Form 10-K{\*\bkmkstart _cp_text_1_42_12112272}{\*\bkmkend _cp_text_1_42_12112272}\plain\cf1\f51\fs20\ql , on January 21, 2018, we entered into an Agreement and Plan of Merger, or the Merger Agreement,\plain\cf1\f51\fs20\ql with BioCryst Pharmaceuticals,\~Inc., a Delaware corporation{\*\bkmkstart _cp_text_1_44_12112272}{\*\bkmkend _cp_text_1_44_12112272}\plain\cf1\f51\fs20\ql , or BioCryst, Nautilus Holdco,\~Inc., a Delaware\plain\cf1\f51\fs20\ql corporation and a direct, wholly owned subsidiary of BioCryst{\*\bkmkstart _cp_text_1_47_12112272}{\*\bkmkend _cp_text_1_47_12112272}\plain\cf1\f51\fs20\ql , or Holdco,\~Island Merger Sub,\~Inc., a Delaware\plain\cf1\f51\fs20\ql corporation and a direct, wholly owned subsidiary of Holdco{\*\bkmkstart _cp_text_1_50_12112272}{\*\bkmkend _cp_text_1_50_12112272}\plain\cf1\f51\fs20\ql , or Merger Sub A, and Boat Merger Sub,\~Inc., a\plain\cf1\f51\fs20\ql Delaware corporation and a direct, wholly owned subsidiary of Holdco{\*\bkmkstart _cp_text_1_53_12112272}{\*\bkmkend _cp_text_1_53_12112272}\plain\cf1\f51\fs20\ql , or Merger Sub B.\~\~Pursuant to the Merger\plain\cf1\f51\fs20\ql Agreement, and subject to the satisfaction or waiver of the conditions specified therein, (a)\~Merger Sub A will be\plain\cf1\f51\fs20\ql merged with and into{\*\bkmkstart _cp_text_1_56_12112272}{\*\bkmkend _cp_text_1_56_12112272}\plain\cf1\f51\fs20\ql us, or the Idera Merger, with us surviving as a wholly owned subsidiary of Holdco, and\plain\cf1\f51\fs20\ql (b)\~Merger Sub B will be merged with and into BioCryst{\*\bkmkstart _cp_text_1_60_12112272}{\*\bkmkend _cp_text_1_60_12112272}\plain\cf1\f51\fs20\ql , or the BioCryst Merger, which we refer to together with\plain\cf1\f51\fs20\ql the Idera Merger{\*\bkmkstart _cp_text_1_66_12112272}{\*\bkmkend _cp_text_1_66_12112272}\plain\cf1\f51\fs20\ql as the Mergers, with BioCryst surviving as a wholly owned subsidiary of Holdco.\~Holdco will be\plain\cf1\f51\fs20\ql renamed prior to the closing of the Mergers.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql At the effective time of the Mergers{\*\bkmkstart _cp_text_1_74_12112272}{\*\bkmkend _cp_text_1_74_12112272}\plain\cf1\f51\fs20\ql , which we refer to as the Effective Time, (i)\~each share of common\plain\cf1\f51\fs20\ql stock, par value $0.001 per share, issued and outstanding immediately prior to the Effective Time (other than the\plain\cf1\f51\fs20\ql shares that are owned by us, BioCryst, Holdco, Merger Sub A or Merger Sub B or any wholly owned subsidiary of\plain\cf1\f51\fs20\ql ours, BioCryst, Holdco, Merger Sub A or Merger Sub B) will be converted into the right to receive 0.20 of a newly\plain\cf1\f51\fs20\ql issued share of common stock, par value $0.01 per share, of Holdco and (ii)\~each share of preferred stock, par value\plain\cf1\f51\fs20\ql $0.01 per share, issued and outstanding immediately prior to the Effective Time (other than the shares that are\plain\cf1\f51\fs20\ql owned by us, BioCryst, Holdco, Merger Sub A or Merger Sub B or any wholly owned subsidiary of ours, BioCryst,\plain\cf1\f51\fs20\ql Holdco, Merger Sub A or Merger Sub B) will be converted into the right to receive an amount of Holdco{\*\bkmkstart _cp_text_1_83_12112272}{\*\bkmkend _cp_text_1_83_12112272}\plain\cf1\f51\fs20\ql common\plain\cf1\f51\fs20\ql stock based on their liquidation preference{\*\bkmkstart _cp_text_1_85_12112272}{\*\bkmkend _cp_text_1_85_12112272}\plain\cf1\f51\fs20\ql .\par\pard\plain\fi594\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_99_12112272}{\*\bkmkend _cp_text_1_99_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql We expect to consummate the Mergers in{\*\bkmkstart _cp_text_4_100_12112272}{\*\bkmkend _cp_text_4_100_12112272}\plain\cf1\f51\fs20\ql the second quarter of 2018{\*\bkmkstart _cp_text_1_101_12112272}{\*\bkmkend _cp_text_1_101_12112272}\plain\cf1\f51\fs20\ql . However, we have prepared this\plain\cf1\f51\fs20\ql Annual Report on Form 10-K and the forward-looking statements contained in this Annual Report on Form 10-K\plain\cf1\f51\fs20\ql as if we were going to remain an independent company.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 2\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf11\f51\fs24\b\ql Research and Development Programs\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The following table summarizes certain information regarding our drug candidates and development\plain\cf1\f51\fs20\ql programs.\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\trqc\clvertalb\cellx2423\cellx3150\clvertalb\cellx5932\cellx6299\clvertalb\cellx9684\clvertalc\cellx9688\trrh66
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clvertalb\cellx2423\cellx3150\clvertalb\cellx5932\cellx6299\clvertalb\cellx9684\clvertalc\cellx9688\trrh66\row}}}
{\trowd\trqc\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2423\cellx3150\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5932\cellx6299\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\b\qc Drug Candidate(s)\cell\pard\plain\intbl\fi528\cf1\f51\fs20\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qc Indication / Application\cell\pard\plain\intbl\fi528\cf1\f51\fs20\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qc Development Status\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2423\cellx3150\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5932\cellx6299\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clvertalc\cellx2423\cellx3150\clbrdrt\brdrs\brdrcf1\clvertalc\cellx5932\cellx6299\clbrdrt\brdrs\brdrcf1\clvertalc\cellx9684\clvertalc\cellx9688\trrh264
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clvertalc\cellx2423\cellx3150\clbrdrt\brdrs\brdrcf1\clvertalc\cellx5932\cellx6299\clbrdrt\brdrs\brdrcf1\clvertalc\cellx9684\clvertalc\cellx9688\trrh264\row}}}
{\trowd\trqc\cellx9686\clvertalc\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\b\i\ql Clinical Programs for the Modulation of Specific Toll-like Receptors\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx9686\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\i\ql Immuno-oncology\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh2970
\pard\plain\intbl\fi396\cf1\f51\fs20\ql IMO-2125\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Anti-PD1 Refractory Metastatic\plain\intbl\cf1\f51\fs20\ql Melanoma\par\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\par\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\par\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\par\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\par\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\par\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Phase 1/2 clinical trial in combination\plain\intbl\cf1\f51\fs20\ql with ipilimumab and pembrolizumab\plain\intbl\cf1\f51\fs20\ql ongoing.\par\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\par\pard\plain\intbl\cf1\f51\fs20\ql Anticipated completion of enrollment in\plain\intbl\cf1\f51\fs20\ql ipilimumab combination arm of the\plain\intbl\cf1\f51\fs20\ql Phase 2 portion of the trial by the end\plain\intbl\cf1\f51\fs20\ql of 2018.\par\pard\plain\intbl\cf1\f51\fs20\ql \~\par\pard\plain\intbl\cf1\f51\fs20\ql Phase 3 clinical trial in combination\plain\intbl\cf1\f51\fs20\ql with ipilimumab initiated in the first\plain\intbl\cf1\f51\fs20\ql quarter of 2018.\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh2970\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\fi396\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh742
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Refractory Solid Tumors\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Phase 1b monotherapy trial in multiple\plain\intbl\cf1\f51\fs20\ql tumor types ongoing.\par\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh742\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\i\ql Rare Diseases\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh742
\pard\plain\intbl\fi396\cf1\f51\fs20\ql IMO-8400\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Dermatomyositis\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Phase 2 clinical trial\u8212?Enrollment\plain\intbl\cf1\f51\fs20\ql complete. Data anticipated to be\plain\intbl\cf1\f51\fs20\ql available in the second quarter of 2018.\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh742\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx9686\clvertalc\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\b\i\ql Nucleic Acid Chemistry Research Programs\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx9686\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\i\ql Rare Diseases\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh1238
\pard\plain\intbl\fi396\cf1\f51\fs20\ql IDRA-008\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Apolipoprotein C-III gene target\plain\intbl\cf1\f51\fs20\ql for treatment of Familial\plain\intbl\cf1\f51\fs20\ql Chylomicronemia Syndrome and\plain\intbl\cf1\f51\fs20\ql Familial Partial Lipodystrophy\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Research / IND-enabling activities\plain\intbl\cf1\f51\fs20\ql underway\u8212?Development decision\plain\intbl\cf1\f51\fs20\ql to be made based on the totality of\plain\intbl\cf1\f51\fs20\ql IND-enabling studies and comparator\plain\intbl\cf1\f51\fs20\ql study with Volanesorsen.\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh1238\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\fi396\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh1238
\pard\plain\intbl\li396\cf1\f51\fs20\ql Nucleic Acid\~\~Chemistry\plain\intbl\li396\cf1\f51\fs20\ql Compound\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Renal Target\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Collaboration with GSK for an\plain\intbl\cf1\f51\fs20\ql undisclosed renal target entered into in\plain\intbl\cf1\f51\fs20\ql 2015. Single candidate selection by\plain\intbl\cf1\f51\fs20\ql GSK for the selected renal target\plain\intbl\cf1\f51\fs20\ql anticipated in the second half of 2018.\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh1238\row}}}
{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh248
\pard\plain\intbl\li396\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\fi528\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
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{\trowd\trqc\cellx2423\cellx3150\cellx5932\cellx6299\cellx9684\clvertalc\cellx9688\trrh742
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\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi792\cf1\f51\fs20\ql Advancements in cancer immunotherapy have included the approval and late-stage development of\plain\cf1\f51\fs20\ql multiple checkpoint inhibitors, which are therapies that target mechanisms by which tumor cells evade detection by\plain\cf1\f51\fs20\ql the immune system. Despite these advancements, many patients fail to respond to these therapies. For instance,\plain\cf1\f51\fs20\ql approximately 50% of patients with melanoma fail to respond to therapy with approved checkpoint inhibitors.\plain\cf1\f51\fs20\ql Current published data suggests that the lack of response to checkpoint inhibition is related to a non-immunogenic\plain\cf1\f51\fs20\ql tumor micro environment. Because TLR9 agonists stimulate the immune system, we believe there is a scientific\plain\cf1\f51\fs20\ql rationale to evaluate the combination of intra-tumoral injection of our TLR9 agonists with checkpoint inhibitors.\plain\cf1\f51\fs20\ql Specifically, we believe intra-tumoral injection of our TLR9 agonists activates a local immune response in the\plain\cf1\f51\fs20\ql injected tumor, which may complement the effect of the systemically administered checkpoint inhibitors. In studies\plain\cf1\f51\fs20\ql in preclinical cancer models conducted in our laboratories, intra-tumoral injection of TLR9 agonists has potentiated\plain\cf1\f51\fs20\ql the anti-tumor activity of multiple checkpoint inhibitors in multiple tumor models. These data have been presented\plain\cf1\f51\fs20\ql at several scientific and medical conferences from 2014 through 2018. We believe these data support evaluation of\plain\cf1\f51\fs20\ql combination regimens including the combination of a TLR9 agonist and a checkpoint inhibitor for the treatment of\plain\cf1\f51\fs20\ql cancer.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs24\b\ql ONGOING CANCER CLINICAL RESEARCH PROGRAMS\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs22\b\ql ILLUMINATE (IMO-2125) Clinical Development\par\pard\plain\cf1\f51\fs24\ql \~\par\pard\plain\fi792\cf1\f51\fs20\ql IMO-2125 is a synthetic phosphorothioate oligonucleotide that acts as a direct agonist of TLR9 to\plain\cf1\f51\fs20\ql stimulate the innate and adaptive immune systems. We are developing IMO-2125 for administration via\plain\cf1\f51\fs20\ql intra-tumoral injection, for the treatment of anti-PD1 refractory metastatic melanoma in combination with\plain\cf1\f51\fs20\ql ipilimumab. We are also investigating the combination of intra-tumoral IMO-2125 in combination with\plain\cf1\f51\fs20\ql pembrolizumab for the treatment of anti-PD1 refractory metastatic melanoma and intratumoral IMO-2125 in\plain\cf1\f51\fs20\ql various solid tumors as monotherapy. We refer to our IMO-2125 development program as the Illuminate\plain\cf1\f51\fs20\ql development program.\~\par\pard\plain\cf1\f51\fs20\ql \~\par\ql{\*\shppict{\pict\pngblip\picw1042\pich32\picscalex46\picscaley46\bliptag-32101099673
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\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are currently developing IMO-2125 for use in combination with checkpoint inhibitors for the treatment\plain\cf1\f51\fs20\ql of\~patients with anti-PD1 refractory metastatic melanoma. We believe, based on internally conducted commercial\plain\cf1\f51\fs20\ql research, that in the United States, by 2025, approximately 20,000 people will have metastatic melanoma and over\plain\cf1\f51\fs20\ql 50% will not have responded to first-line anti-PD1 therapy. We also believe TLR9 agonists may be useful in other\plain\cf1\f51\fs20\ql solid tumor types that are refractory to anti-PD1 treatment due in part to low mutation load and low dendritic cell\plain\cf1\f51\fs20\ql infiltration.\~\~ We believe, based on internally conducted commercial research, that in the United States, by 2025,\plain\cf1\f51\fs20\ql approximately 160,000 people will have tumor types that are addressable with current immunotherapy and\plain\cf1\f51\fs20\ql approximately 70,000 of those people will have tumor types that are anti-PD1 refractory.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In June 2017, the U.S. Food and Drug Administration, or FDA, granted Orphan Drug Designation for\plain\cf1\f51\fs20\ql IMO-2125 for the treatment of melanoma Stages IIb to IV.\~\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In November 2017, the FDA granted Fast Track designation for IMO-2125 for the treatment of anti-PD1\plain\cf1\f51\fs20\ql refractory metastatic melanoma in combination with ipilimumab therapy.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\ql{\*\shppict{\pict\pngblip\picw217\pich76\picscalex38\picscaley38\bliptag-32101099673
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\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\li594\cf1\f51\fs20\b\i\ql Phase 1/2 Trial of IMO-2125 in Combination with Ipilimumab or Pembrolizumab in Patients with\plain\li594\cf1\f51\fs20\b\i\ql Anti-PD1 Refractory Metastatic Melanoma\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In December 2015, we initiated a Phase 1/2 clinical trial to assess the safety and efficacy of IMO-2125,\plain\cf1\f51\fs20\ql administered intra-tumorally, in combination with ipilimumab, in patients with metastatic melanoma (refractory to\plain\cf1\f51\fs20\ql treatment with a PD1 inhibitor, also referred to as anti-PD1 refractory), which we refer to as Illuminate 204. We\plain\cf1\f51\fs20\ql subsequently amended the trial protocol to enable an additional arm to study the combination of IMO-2125 with\par\pard\plain\sb528\cf1\f51\fs20\qc 4\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql pembrolizumab, an anti-PD1 antibody marketed as Keytruda\u174? by Merck & Co., in the same patient\plain\cf1\f51\fs20\ql population. In this clinical trial, IMO-2125 is administered intra-tumorally into a selected tumor lesion at weeks 1,\plain\cf1\f51\fs20\ql 2, 3, 5, 8, 11, 17, 23 and 29 (total of 9 doses) together with the standard dosing regimen of ipilimumab or\plain\cf1\f51\fs20\ql pembrolizumab, administered intravenously. For patients who lack superficially accessible disease for injection,\plain\cf1\f51\fs20\ql IMO-2125 is administered via injection into deep lesions, such as liver metastases, using interventional radiology\plain\cf1\f51\fs20\ql guidance.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The trial was initiated at the University of Texas, MD Anderson Cancer Center, or MD Anderson, under the\plain\cf1\f51\fs20\ql strategic research alliance we entered into with MD Anderson in June 2015, and additional sites have been added\plain\cf1\f51\fs20\ql through 2017.\~We anticipate that more sites will be added, to bring the total number of participating sites for the\plain\cf1\f51\fs20\ql trial to ten. The primary objectives of the Phase 1 portion of the trial include characterizing the safety of the\plain\cf1\f51\fs20\ql combinations and determining the recommended Phase 2 dose. A secondary objective of the Phase 1 portion of the\plain\cf1\f51\fs20\ql trial is describing the anti-tumor activity of IMO-2125 when administered intra-tumorally in combination with\plain\cf1\f51\fs20\ql ipilimumab or pembrolizumab. The primary objective of the Phase 2 portion of the trial is to determine the activity\plain\cf1\f51\fs20\ql of the combinations utilizing immune-related response criteria.\~\~The secondary objectives of the Phase 2 portion of\plain\cf1\f51\fs20\ql the trial include the assessment of treatment response using RECIST v1.1 criteria and to continue to characterize the\plain\cf1\f51\fs20\ql safety of the combinations. In the Phase 1 portion of the trial, serial biopsies are being taken of selected injected\plain\cf1\f51\fs20\ql and non-injected tumor lesions pre- and post-24 hours of the first dose of IMO-2125, as well as at 8 and 13\plain\cf1\f51\fs20\ql weeks, to assess immune changes and response assessments. In the Phase 2 portion of the trial, biopsies are\plain\cf1\f51\fs20\ql optional.\par\pard\plain\ri264\cf1\f51\fs20\ql \~\par\pard\plain\li594\cf1\f51\fs20\i\ql Phase 1/2 Trial of IMO-2125 in Patients with Anti-PD1 Refractory Metastatic Melanoma: Combination with\plain\li594\cf1\f51\fs20\i\ql Ipilimumab Arm\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In the Phase 1 portion of the ipilimumab arm of our Phase 1/2 clinical trial of IMO-2125, escalating doses of\plain\cf1\f51\fs20\ql IMO-2125 ranging from 4 mg through 32 mg were evaluated. In April 2017, we completed IMO-2125 dose\plain\cf1\f51\fs20\ql escalation and based on the safety and efficacy data and data from translational immune parameters, selected the 8\plain\cf1\f51\fs20\ql mg dose level as the recommended dose level for the Phase 2 expansion phase of the IMO-2125\u8211?ipilimumab\plain\cf1\f51\fs20\ql combination.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In September 2017, we disclosed at the 2017 European Society for Medical Oncology Congress, final results\plain\cf1\f51\fs20\ql from the 18 patients that were evaluated with the IMO-2125\u8211?ipilimumab combination in the Phase 1 dose\plain\cf1\f51\fs20\ql escalation portion of the trial.\~\~Each of these patients but one had progressed on nivolumab or pembrolizumab prior\plain\cf1\f51\fs20\ql to enrollment in the trial.\~\~As of May 31, 2017, the safety data cutoff date for the presentation, the combination of\plain\cf1\f51\fs20\ql IMO-2125 and ipilimumab had been well tolerated at all dose levels studied.\~\~No dose-limiting toxicities had been\plain\cf1\f51\fs20\ql observed and the maximum tolerated dose was not reached.\~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In January 2018, we provided an update on our Phase 1/2 trial evaluating IMO-2125 in combination with\plain\cf1\f51\fs20\ql ipilimumab at the recommended 8 mg dose level, noting that 21 patients had been dosed.\~\~As of November 3, 2017,\plain\cf1\f51\fs20\ql the data cut-off date for the presentation, of the 10 patients that had been treated at the 8 mg dose of IMO-2125\plain\cf1\f51\fs20\ql and who had at least one post-baseline disease assessment, four had a complete response or partial response under\plain\cf1\f51\fs20\ql RECIST v.1.1 criteria, with the one patient who had a complete response continuing off active treatment for more\plain\cf1\f51\fs20\ql than one year, and remaining disease free. One of the 10 patients had a response which had not been confirmed as\plain\cf1\f51\fs20\ql of November 3, 2017 (as required by RECIST). Additionally, two other patients that were treated at the 8 mg dose\plain\cf1\f51\fs20\ql experienced stable disease for at least 24 weeks, which is considered to represent meaningful clinical benefit.\~\~Also,\plain\cf1\f51\fs20\ql as of the response data cutoff date, one patient who was treated at the 4 mg dose had an ongoing partial response\plain\cf1\f51\fs20\ql and had been off active treatment for more than one year.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In April 2017, we initiated enrollment in the Phase 2 portion of the ipilimumab arm of our Phase 1/2 clinical\plain\cf1\f51\fs20\ql trial of IMO-2125 with the 8 mg dose of intra-tumoral IMO-2125. The Phase 2 portion of the trial utilizes a\plain\cf1\f51\fs20\ql Simon two-stage design to evaluate the objective response rate of IMO-2125 in combination with ipilimumab,\plain\cf1\f51\fs20\ql compared to historical data for ipilimumab alone in the anti-PD1 refractory metastatic melanoma population. With\plain\cf1\f51\fs20\ql the responses noted above, the trial has met the pre-specified futility assessment and advanced into the second stage\plain\cf1\f51\fs20\ql of the Phase 2 portion. We anticipate that the Phase 2 portion of the trial will include a total of up to 60 patients\plain\cf1\f51\fs20\ql dosed at the 8 mg dose, including some patients from the Phase 1 dose escalation portion who meet the efficacy\plain\cf1\f51\fs20\ql criteria for the Phase 2 population, and that these patients may be fully accrued by the end of 2018.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\li594\cf1\f51\fs20\ql \~\par\pard\plain\li594\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 5\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\li594\cf1\f51\fs20\i\ql Phase 1/2 Trial of IMO-2125 in Patients with Anti-PD1 Refractory Metastatic Melanoma: Combination with\plain\li594\cf1\f51\fs20\i\ql Pembrolizumab Arm\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In the Phase 1 portion of the pembrolizumab arm of our Phase 1/2 clinical trial of IMO-2125, we are\plain\cf1\f51\fs20\ql evaluating escalating doses of IMO-2125 ranging from 8 mg through 32 mg.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have completed enrollment of a total of six patients in the 8 mg and 16 mg dosing cohorts in the Phase 1\plain\cf1\f51\fs20\ql dose escalation portion of the pembrolizumab\~arm of the trial and are continuing to enroll patients in the 32 mg\plain\cf1\f51\fs20\ql dosing cohort. One patient who was treated at the 16 mg dose has an ongoing partial response by RECIST v1.1\plain\cf1\f51\fs20\ql criteria.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\ql\li594{\*\shppict{\pict\pngblip\picw218\pich77\picscalex37\picscaley37\bliptag-32101099673
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\pard\plain\li594\cf1\f51\fs20\ql \~\par\pard\plain\li594\cf1\f51\fs12\ql \~\par\pard\plain\li594\cf1\f51\fs20\b\i\ql Phase 3 Trial of IMO-2125 in Combination with Ipilimumab in Patients with Anti-PD1 Refractory\plain\li594\cf1\f51\fs20\b\i\ql Metastatic Melanoma\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In the first quarter of 2018, we initiated a Phase 3 trial of the IMO-2125\u8211?ipilimumab combination in\plain\cf1\f51\fs20\ql patients with anti-PD1 refractory metastatic melanoma, which we refer to as Illuminate 301.\~\~We expect that this\plain\cf1\f51\fs20\ql trial will compare the results of the IMO-2125\u8211?ipilimumab combination to those of ipilimumab alone in a\plain\cf1\f51\fs20\ql 1:1 randomization, will have a sample size of approximately 300 patients and will be conducted at approximately 80\plain\cf1\f51\fs20\ql sites worldwide, which are selected to not overlap with the trial sites for Illuminate 204.\~\~The primary endpoints of\plain\cf1\f51\fs20\ql the trial are overall response rate (ORR) by RECIST v1.1 and median overall survival (OS).\~\~Key secondary\plain\cf1\f51\fs20\ql endpoints include ORR by irRECIST, durable response rate (DRR), time to response, progression free survival\plain\cf1\f51\fs20\ql (PFS) and patient reported outcome (PRO) using a validated scale.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have held discussions with and plan to continue to engage with regulatory authorities regarding the paths\plain\cf1\f51\fs20\ql to registration for IMO-2125 in combination with ipilimumab in anti-PD1 refractory metastatic melanoma patients,\plain\cf1\f51\fs20\ql including potentially through an accelerated approval process based on an interim analysis of the Phase 3 trial with\plain\cf1\f51\fs20\ql the final analysis providing the confirmatory data for full approval.\~\~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\ql{\*\shppict{\pict\pngblip\picw1042\pich32\picscalex46\picscaley46\bliptag-32101099673
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\par\pard\plain\fi594\cf1\f51\fs12\ql \~\par\pard\plain\li594\cf1\f51\fs20\b\i\ql Phase 1b Trial of Intra-tumoral IMO-2125 Monotherapy in Patients with Refractory Solid Tumors\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In March 2017, we initiated a Phase 1 dose escalation trial of IMO-2125 administered intra-tumorally as a\plain\cf1\f51\fs20\ql monotherapy in multiple tumor types, which we refer to as Illuminate 101.\~\~In this trial, IMO-2125 is administered\plain\cf1\f51\fs20\ql intra-tumorally on days 1, 8 and 15 of cycle 1 and on day 1 of each subsequent 21-day cycle, up to 17 cycles (19\plain\cf1\f51\fs20\ql total doses).\~\~We anticipate enrolling dose-escalation cohorts of approximately 8 patients at doses of 8mg (cohort 1),\plain\cf1\f51\fs20\ql 16mg (cohort 2), 23mg (cohort 3) and 32mg (cohort 4).\~\~A fifth cohort will be enrolled based on the recommended\plain\cf1\f51\fs20\ql Phase 2 dose.\~\~After the last patient in each cohort reaches day 21 of the 21-day dose-limiting toxicity period, the\plain\cf1\f51\fs20\ql Cohort Review Committee will review safety and provide a recommendation regarding dose escalation to the next\plain\cf1\f51\fs20\ql dose.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have completed enrollment in the first and second cohorts and in February 2018, based on the\plain\cf1\f51\fs20\ql recommendation by the Cohort Review Committee, have begun enrolling in the third cohort. Additionally, we are\plain\cf1\f51\fs20\ql enrolling in the melanoma expansion cohort to assess the clinical activity of single agent intratumoral IMO-2125\plain\cf1\f51\fs20\ql (8mg dose) in patients with metastatic melanoma which has progressed on or after treatment with a PD-(L)1\plain\cf1\f51\fs20\ql inhibitor.\~ This cohort will enroll up to 22 subjects.\~ The melanoma expansion cohort will use a Simon\u8217?s\plain\cf1\f51\fs20\ql Optimal Two-Stage design to test for clinically and statistically relevant clinical activity.\~ The melanoma expansion\plain\cf1\f51\fs20\ql cohort will stop if an interim futility analysis shows there is insufficient evidence of a clinically relevant response\plain\cf1\f51\fs20\ql rate after 8 subjects (Stage 1).\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 6\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~\par\ql{\*\shppict{\pict\pngblip\picw286\pich65\picscalex61\picscaley61\bliptag-32101099673
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\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql A rare disease is defined by the Orphan Drug Act of 1983 as a disorder or condition that affects less than\plain\cf1\f51\fs20\ql 200,000 persons in the United States.\~\~However, most rare diseases, affect far fewer persons. There are numerous\plain\cf1\f51\fs20\ql rare and ultra-rare diseases that currently have no approved drug therapy and for which no therapies are currently\plain\cf1\f51\fs20\ql in development. Patients suffering from these diseases often have a high unmet medical need with significant\plain\cf1\f51\fs20\ql morbidity and/or mortality.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs24\b\ql ONGOING RARE DISEASE RESEARCH PROGRAMS\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs22\b\ql IMO-8400 in Rare Diseases\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have initiated clinical development of IMO-8400 for the treatment of rare diseases and have selected\plain\cf1\f51\fs20\ql dermatomyositis as our lead clinical target for which we are developing IMO-8400. We selected this indication for\plain\cf1\f51\fs20\ql development based on the reported increase in TLR expression in this disease state, expression of cytokines\plain\cf1\f51\fs20\ql indicative of key TLR-mediated pathways and the presence of auto-antibodies that can induce TLR-mediated\plain\cf1\f51\fs20\ql immune responses.\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql We considered that multiple independent research studies across a broad range of autoimmune diseases,\plain\cf1\f51\fs20\ql including both dermatomyositis and psoriasis, have demonstrated that the over-activation of TLRs plays a critical\plain\cf1\f51\fs20\ql role in disease maintenance and progression. In autoimmune diseases, endogenous nucleic acids released from\plain\cf1\f51\fs20\ql damaged or dying cells initiate signaling cascades through TLRs, leading to the induction of multiple\plain\cf1\f51\fs20\ql pro-inflammatory cytokines. This inflammation causes further damage to the body\u8217?s own tissues and organs\plain\cf1\f51\fs20\ql and the release of more self-nucleic acids, creating a self-sustaining autoinflammatory cycle that contributes to\plain\cf1\f51\fs20\ql chronic inflammation in the affected tissue, promoting disease progression.\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql We believe we demonstrated proof of concept for our approach of using TLRs to inhibit the over-activation\plain\cf1\f51\fs20\ql of specific TLRs for the treatment of psoriasis and potentially other autoimmune diseases in a randomized,\plain\cf1\f51\fs20\ql double-blind, placebo-controlled Phase 2 clinical trial of IMO-8400 that we conducted in patients with moderate to\plain\cf1\f51\fs20\ql severe plaque psoriasis, a well-characterized autoimmune disease. In this trial, we evaluated IMO-8400 at four\plain\cf1\f51\fs20\ql subcutaneous dose levels of 0.075 mg/kg, 0.15 mg/kg, 0.3 mg/kg, and 0.6 mg/kg, versus placebo, administered once\plain\cf1\f51\fs20\ql weekly for 12 weeks in 46 patients. The trial met its primary objective as IMO-8400 was well tolerated at all dose\plain\cf1\f51\fs20\ql levels with no treatment-related discontinuations, treatment-related serious adverse events or dose reductions. The\plain\cf1\f51\fs20\ql trial also met its secondary objective of demonstrating clinical activity in psoriasis patients, as assessed by the\plain\cf1\f51\fs20\ql Psoriasis Area Severity Index.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\ql{\*\shppict{\pict\pngblip\picw1042\pich32\picscalex46\picscaley46\bliptag-32101099673
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\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql Dermatomyositis is a rare, debilitating, inflammatory muscle and skin disease associated with significant\plain\cf1\f51\fs20\ql morbidity, decreased quality of life and an increased risk of premature death. While the cause of dermatomyositis is\plain\cf1\f51\fs20\ql not well understood, the disease process involves immune system attacks against muscle and skin that lead to\plain\cf1\f51\fs20\ql inflammation and tissue\~damage. Major symptoms can include progressive muscle weakness, severe skin rash,\plain\cf1\f51\fs20\ql calcium deposits under the skin (calcinosis), difficulty swallowing (dysphagia) and interstitial lung disease. We\plain\cf1\f51\fs20\ql believe, based on internally conducted commercial research, that dermatomyositis affects approximately 25,000\plain\cf1\f51\fs20\ql people in the United States, and is about twice as common in women as men, with a typical age of onset between\plain\cf1\f51\fs20\ql 45 and 65 years in adults. Dermatomyositis represents one form of myositis, a spectrum of inflammatory muscle\plain\cf1\f51\fs20\ql diseases that also includes juvenile dermatomyositis, polymyositis and inclusion body myositis.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs28\b\ql PIONEER\~\par\pard\plain\fi594\cf1\f51\fs20\b\ql Phase 2 Trial of IMO-8400 in Patients with Dermatomyositis\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql In December 2015, we initiated a Phase 2, randomized, double-blind, placebo-controlled clinical trial\plain\cf1\f51\fs20\ql designed to assess the safety, tolerability and treatment effect of IMO-8400 in adult patients with dermatomyositis.\par\pard\plain\sb528\cf1\f51\fs20\qc 7\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql Eligibility criteria included evidence of active skin involvement. Patients enrolled in the trial were randomized to\plain\cf1\f51\fs20\ql one of three groups to receive once weekly subcutaneous injections of: placebo, 0.6 mg/kg of IMO-8400 or 1.8\plain\cf1\f51\fs20\ql mg/kg of IMO-8400, in each case, for a period of 24 weeks. The trial is being conducted at 21 centers in the\plain\cf1\f51\fs20\ql United States, the United Kingdom and Hungary. We concluded enrollment in the trial at 30 patients and expect full\plain\cf1\f51\fs20\ql Phase 2 trial data in the second quarter of 2018 consisting of top-line primary and secondary endpoint analysis,\plain\cf1\f51\fs20\ql complete tables and listings and translational medicine data. The primary efficacy endpoint is the change from\plain\cf1\f51\fs20\ql baseline in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), a validated outcome measure\plain\cf1\f51\fs20\ql of skin disease. Additional exploratory endpoints include muscle strength and function (which are among the\plain\cf1\f51\fs20\ql International Myositis Assessment & Clinical Studies Group (IMACS) core set measures), patient-reported quality\plain\cf1\f51\fs20\ql of life and biochemical markers of disease activity.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs24\b\ql DISCOVERY PROGRAMS\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs22\b\i\ql Nucleic Acid Chemistry Research\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are developing our nucleic acid chemistry technology to \u8220?turn off\u8221? the mRNA associated\plain\cf1\f51\fs20\ql with disease causing genes. We have designed gene-silencing oligonucleotides to specifically address challenges\plain\cf1\f51\fs20\ql associated with earlier generation antisense and RNAi technologies.\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our focus is on creating candidates targeted to specific genes to treat cancer and rare diseases. Our key\plain\cf1\f51\fs20\ql considerations in identifying disease indications and gene targets in our nucleic acid chemistry research program\plain\cf1\f51\fs20\ql include: strong evidence that the disease is caused by a specific protein; clear criteria to identify a target patient\plain\cf1\f51\fs20\ql population; biomarkers for early assessment of clinical proof of concept; a targeted therapeutic mechanism of action;\plain\cf1\f51\fs20\ql unmet medical need to allow for a rapid development path to approval and commercial opportunity.\~To date, we\plain\cf1\f51\fs20\ql have created 22 novel nucleic acid chemistry compounds for specific gene targets that are potentially applicable\plain\cf1\f51\fs20\ql across a wide variety of therapeutic areas.\~\~These areas include rare diseases, oncology, autoimmune disorders,\plain\cf1\f51\fs20\ql metabolic conditions, single point mutations and others.\~Our current activities with respect to these compounds range\plain\cf1\f51\fs20\ql from cell culture through investigational new drug, or IND, application-enabling toxicology.\par\pard\plain\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql IDRA-008 Development\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In January 2017, we announced that we had selected IDRA-008 as our first nucleic acid chemistry research\plain\cf1\f51\fs20\ql program candidate that we plan to enter into clinical development and that we were planning to develop IDRA-008\plain\cf1\f51\fs20\ql for a well-established liver target. In January 2018, we announced that IDRA-008 was targeted at Apolipoprotein\plain\cf1\f51\fs20\ql C-III (APOC-III) and was being developed for the treatment of Familial Chylomicronemia Syndrome (FCS) and\plain\cf1\f51\fs20\ql Familial Partial Lipodystrophy (FPL) which have available pre-clinical animal models and well-known clinical\plain\cf1\f51\fs20\ql endpoints.\~\par\pard\plain\cf1\f51\fs20\ql Our development decision for IDRA-008 will be based on the totality of data from our pre-clinical toxicology and\plain\cf1\f51\fs20\ql IND-enabling studies and data from our pre-clinical pharmacology study in a Cyno-model (non-human primates)\plain\cf1\f51\fs20\ql comparing IDRA-008 to the competitive development asset Volanesorsen.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Nucleic Acid Chemistry Compound\u8212?Undisclosed Renal Target\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In November 2015, we entered into a collaboration and license agreement with GlaxoSmithKline Intellectual\plain\cf1\f51\fs20\ql Property Development Limited, or GSK, to license, research, develop and commercialize pharmaceutical compounds\plain\cf1\f51\fs20\ql from our nucleic acid chemistry technology for the treatment of selected targets in renal disease, which agreement\plain\cf1\f51\fs20\ql we refer to as the GSK Agreement.\~Under this collaboration, we are creating multiple development candidates to\plain\cf1\f51\fs20\ql address the target designated by GSK in connection with entering into the GSK Agreement.\~\~From the population of\plain\cf1\f51\fs20\ql identified development candidates, GSK may designate one development candidate in its sole discretion to move\plain\cf1\f51\fs20\ql forward into clinical development.\~We expect GSK to select a development candidate in the second half of 2018.\plain\cf1\f51\fs20\ql Once GSK designates a development candidate, GSK would be solely responsible for the development and\plain\cf1\f51\fs20\ql commercialization activities for that designated development candidate.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs24\b\ql OTHER PROGRAMS\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql IMO-9200 for Autoimmune Disease\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have developed a second novel synthetic oligonucleotide antagonist of TLR7, TLR8, and TLR9,\plain\cf1\f51\fs20\ql IMO-9200, as a drug candidate for potential use in selected autoimmune disease indications. In 2015, we completed\plain\cf1\f51\fs20\ql a\par\pard\plain\sb528\cf1\f51\fs20\qc 8\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql Phase 1 clinical trial of IMO-9200 in healthy subjects as well as additional preclinical studies of IMO-9200 for\plain\cf1\f51\fs20\ql autoimmune diseases. In 2015, we determined not to proceed with the development of IMO-9200 because the large\plain\cf1\f51\fs20\ql autoimmune disease indications for which IMO-9200 had been developed did not fit within the strategic focus of\plain\cf1\f51\fs20\ql our company. In November 2016, we entered into an exclusive license and collaboration agreement with Vivelix\plain\cf1\f51\fs20\ql Pharmaceuticals, Ltd., or Vivelix, granting Vivelix worldwide rights to develop and market IMO-9200 for\plain\cf1\f51\fs20\ql non-malignant gastrointestinal disorders, which agreement we refer to as the Vivelix Agreement.\par\pard\plain\cf11\f51\fs24\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Collaborative Alliances\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition to our current alliances, we may explore potential collaborative alliances to support development\plain\cf1\f51\fs20\ql and commercialization of our TLR agonists and antagonists. We may also seek to enter into additional collaborative\plain\cf1\f51\fs20\ql alliances with pharmaceutical companies with respect to applications of our nucleic acid chemistry research\plain\cf1\f51\fs20\ql program. Our current alliances include collaborations with Vivelix, GSK, and Abbott Molecular.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\qj Vivelix\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql In November\~2016, we entered into the Vivelix Agreement, granting Vivelix worldwide rights to develop and\plain\cf1\f51\fs20\ql market IMO-9200, an antagonist of TLR 7, 8 and 9, for non-malignant gastrointestinal disorders (the GI Field or\plain\cf1\f51\fs20\ql Field as defined in the Vivelix Agreement) and certain back-up compounds to IMO-9200.\~\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql In accordance with the Vivelix Agreement, a Joint Research Committee, or JRC, was formed with equal\plain\cf1\f51\fs20\ql representation from us and Vivelix. The responsibilities of the JRC, include, but are not limited to monitoring the\plain\cf1\f51\fs20\ql progress of the research program, advising on the designation of back-up compounds, sharing information between\plain\cf1\f51\fs20\ql the parties and dealing with disputes that may arise between the parties. If a dispute cannot be resolved by the JRC,\plain\cf1\f51\fs20\ql Vivelix has final decision making authority.\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql In connection with the Vivelix Agreement, we transferred certain drug material to Vivelix for\plain\cf1\f51\fs20\ql Vivelix\u8217?s use in its development activities.\~\~Vivelix is solely responsible for the development and\plain\cf1\f51\fs20\ql commercialization of IMO-9200 and any designated back-up compounds to IMO-9200.\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql If requested by Vivelix pursuant to the Vivelix Agreement, we will create, characterize and perform research\plain\cf1\f51\fs20\ql on back-up compounds.\~\~Such activity is to be mutually agreed upon and moderated by the JRC.\~\~The research\plain\cf1\f51\fs20\ql period commenced with the execution of the agreement and may last for up to three years.\~\~During the research\plain\cf1\f51\fs20\ql period, the parties will agree on the number of full time equivalents to work on the program.\~\~Vivelix will reimburse\plain\cf1\f51\fs20\ql us at an annual market rate for the services rendered.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Vivelix has certain rights under the agreement whereby it may (i) exercise the right of first refusal, (ii) the\plain\cf1\f51\fs20\ql right of first negotiation to obtain an exclusive license for any compound controlled by us that has activity in the\plain\cf1\f51\fs20\ql field of inflammatory bowel disease and (iii) the right to request an expanded Field beyond the GI Field.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi792\cf1\f51\fs20\ql Under the terms of the Vivelix Agreement, we received an upfront, non-refundable fee of $15 million.\~ In\plain\cf1\f51\fs20\ql addition, we will be eligible for future IMO-9200 related development, regulatory and sales milestone payments\plain\cf1\f51\fs20\ql totaling up to $140 million, including development and regulatory milestones totaling up to $65 million and sales\plain\cf1\f51\fs20\ql milestones totaling up to $75 million, and escalating royalties ranging from the mid single-digits to low\plain\cf1\f51\fs20\ql double-digits of global net sales, which percentages are subject to reduction under agreed upon circumstances.\plain\cf1\f51\fs20\ql Additionally, under the terms of the agreement and if requested by and at Vivelix\u8217?s expense, we are\plain\cf1\f51\fs20\ql responsible for developing potential back-up compounds to IMO-9200.\~ As it relates to back-up compounds, we\plain\cf1\f51\fs20\ql will be eligible for related designation payments and development, regulatory sales and milestone payments totaling\plain\cf1\f51\fs20\ql up to $52.5 million, including development and regulatory milestones totaling up to $35 million and sales\plain\cf1\f51\fs20\ql milestones totaling up to $17.5 million, and escalating royalties ranging from the mid single-digits to low\plain\cf1\f51\fs20\ql double-digits of global net sales, which percentages are subject to reduction under agreed upon circumstances.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql GlaxoSmithKline Intellectual Property Development Limited\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In November\~2015, we entered into the GSK Agreement to license, research, develop and commercialize\plain\cf1\f51\fs20\ql pharmaceutical compounds from our nucleic acid chemistry technology for the treatment of selected targets in renal\plain\cf1\f51\fs20\ql disease. The initial collaboration term is currently anticipated to last between two and four years from signing. In\plain\cf1\f51\fs20\ql connection with the GSK Agreement, GSK identified an initial target for us to attempt to identify a\par\pard\plain\sb528\cf1\f51\fs20\qc 9\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql potential population of development candidates to address such target under a mutually agreed upon research plan,\plain\cf1\f51\fs20\ql currently estimated to take 36 months to complete. From the population of identified development candidates, GSK\plain\cf1\f51\fs20\ql may designate one development candidate in its sole discretion to move forward into clinical development. Once\plain\cf1\f51\fs20\ql GSK designates a development candidate, GSK would be solely responsible for the development and\plain\cf1\f51\fs20\ql commercialization activities for that designated development candidate.\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql The GSK Agreement also provided GSK with the option to select up to two additional targets at any time\plain\cf1\f51\fs20\ql during the first two years of the agreement, for further research under mutually agreed upon research plans. Upon\plain\cf1\f51\fs20\ql selecting additional targets, GSK then had the option to designate one development candidate for each additional\plain\cf1\f51\fs20\ql target, at which time GSK would have sole responsibility to develop and commercialize each such designated\plain\cf1\f51\fs20\ql development candidate. As of December 31, 2017, GSK had not selected any additional targets for research and the\plain\cf1\f51\fs20\ql option period in which GSK could select additional targets had expired.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql In accordance with the GSK Agreement, a Joint Steering Committee, or JSC, was formed with equal\plain\cf1\f51\fs20\ql representation from us and GSK. The responsibilities of the JSC, include, but are not limited to monitoring the\plain\cf1\f51\fs20\ql progress of the collaboration, reviewing research plans and dealing with disputes that may arise between the parties.\plain\cf1\f51\fs20\ql If a dispute cannot be resolved by the JSC, GSK has final decision making authority.\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Under the terms of the GSK Agreement, we received a $2.5 million upfront, non-refundable, non-creditable\plain\cf1\f51\fs20\ql cash payment upon the execution of the GSK Agreement.\~\~Additionally, we were eligible to receive a total of up to\plain\cf1\f51\fs20\ql approximately $100 million in upfront, license, research, clinical development and commercialization milestone\plain\cf1\f51\fs20\ql payments, of which $9 million of these milestone payments would have been payable by GSK upon the\plain\cf1\f51\fs20\ql identification of the additional targets, the completion of current and future research plans and the designation of\plain\cf1\f51\fs20\ql development candidates and $89 million would have been payable by GSK upon the achievement of clinical\plain\cf1\f51\fs20\ql milestones and commercial milestones. As a result of GSK not selecting additional targets during the two-year\plain\cf1\f51\fs20\ql option period, we are eligible to receive a total of up to approximately $20 million in upfront, license, research,\plain\cf1\f51\fs20\ql clinical development and commercialization milestone payments, of which $1 million of these milestone payments\plain\cf1\f51\fs20\ql would be payable by GSK upon the designation of a development candidate from the initial target and $17 million\plain\cf1\f51\fs20\ql would be payable by GSK upon the achievement of clinical milestones and commercial milestones. In addition, we\plain\cf1\f51\fs20\ql are eligible to receive royalty payments based on net sales of licensed products following commercialization at\plain\cf1\f51\fs20\ql varying rates of up to five percent on annual net sales, as defined in the GSK Agreement.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Abbott Molecular\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In May 2014, we entered into a development and commercialization agreement with Abbott Molecular for the\plain\cf1\f51\fs20\ql development of an in vitro companion diagnostic for use in our clinical development programs to treat certain\plain\cf1\f51\fs20\ql genetically defined forms of B-cell lymphoma with IMO-8400. The agreement provides for the development and\plain\cf1\f51\fs20\ql subsequent commercialization by Abbott Molecular of a companion diagnostic test utilizing polymerase chain\plain\cf1\f51\fs20\ql reaction technology to identify with high sensitivity and specificity the presence in tumor biopsy samples of the\plain\cf1\f51\fs20\ql oncogenic mutation referred to scientifically as MYD88 L265P. Under the agreement, Abbott Molecular is primarily\plain\cf1\f51\fs20\ql responsible for developing and obtaining regulatory approvals for the companion diagnostic in accordance with an\plain\cf1\f51\fs20\ql agreed development plan and regulatory plan and for making the companion diagnostic test commercially available\plain\cf1\f51\fs20\ql in accordance with an agreed commercialization plan. Abbott Molecular will retain all proceeds from\plain\cf1\f51\fs20\ql commercialization of the companion diagnostic test. Subject to the terms of the agreement, we are required to pay\plain\cf1\f51\fs20\ql Abbott Molecular fees and fund Abbott Molecular\u8217?s development of the companion diagnostic test in an\plain\cf1\f51\fs20\ql approximate aggregate amount of $6.7 million over an approximately five year development period, which includes\plain\cf1\f51\fs20\ql clinical trial site costs and Abbott Molecular\u8217?s costs of preparation and filing fees for regulatory submissions\plain\cf1\f51\fs20\ql for the companion diagnostic with the FDA. This amount is subject to increase if Abbott Molecular incurs\plain\cf1\f51\fs20\ql additional expenses in order to meet unexpected material requirements or obligations not included in the agreement\plain\cf1\f51\fs20\ql or if we are required to conduct additional or different clinical trials which result in Abbott Molecular incurring\plain\cf1\f51\fs20\ql additional costs.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The parties\u8217? activities pursuant to the agreed development, regulatory and commercialization plans are\plain\cf1\f51\fs20\ql governed by a joint steering committee, with Abbott Molecular retaining final decision making authority, subject to\plain\cf1\f51\fs20\ql its obligations under the agreement, for development, manufacture and marketing of the companion diagnostic and\plain\cf1\f51\fs20\ql our retaining final decision making authority, subject to our obligations under the agreement, for the development,\plain\cf1\f51\fs20\ql manufacture and marketing of IMO-8400.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 10\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\ql Under the agreement, each party grants the other party specified intellectual property licenses to enable the\plain\cf1\f51\fs20\ql other party to perform its obligations and exercise its rights under the agreement, including license grants enabling\plain\cf1\f51\fs20\ql Abbott Molecular to develop and commercialize the companion diagnostic test for use with IMO-8400 and enabling\plain\cf1\f51\fs20\ql us to develop and commercialize IMO-8400 with Abbott Molecular\u8217?s companion diagnostic test. The\plain\cf1\f51\fs20\ql licenses granted by the parties to one another generally survive termination of the agreement. Abbott Molecular\plain\cf1\f51\fs20\ql remains free to develop its companion diagnostic test for use with third party therapeutic products, and we remain\plain\cf1\f51\fs20\ql free to engage third party diagnostics companies to develop other companion diagnostic tests for use with\plain\cf1\f51\fs20\ql IMO-8400.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are permitted to terminate the agreement upon 90 days written notice to Abbott Molecular and, under\plain\cf1\f51\fs20\ql circumstances specified in the agreement, payment of a termination fee and wind-down costs. The parties also may\plain\cf1\f51\fs20\ql terminate the agreement based on uncured material breaches by or the bankruptcy or insolvency of the other party,\plain\cf1\f51\fs20\ql and each party has the right to terminate the agreement in the event of specified permanent injunctions based on\plain\cf1\f51\fs20\ql infringement of third party intellectual property rights. In September 2016, we suspended clinical development of\plain\cf1\f51\fs20\ql IMO-8400 for B-cell lymphomas. However, we have maintained our relationship with Abbott under the agreement\plain\cf1\f51\fs20\ql as we may explore potential collaborative alliances to support the development of IMO-8400 for B-cell\plain\cf1\f51\fs20\ql lymphomas.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Academic and Research Collaborations\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have entered into research collaborations with scientists at leading academic research institutions. These\plain\cf1\f51\fs20\ql research collaborations allow us to augment our internal research capabilities and obtain access to specialized\plain\cf1\f51\fs20\ql knowledge and expertise. In general, our research collaborations may require us to supply compounds and pay\plain\cf1\f51\fs20\ql various amounts to support the research. Under these research agreements, if a collaborator, solely or jointly with\plain\cf1\f51\fs20\ql us, creates any invention, we may own exclusively such invention, have an automatic paid-up, royalty-free\plain\cf1\f51\fs20\ql non-exclusive license or have an option to negotiate an exclusive, worldwide, royalty-bearing license to such\plain\cf1\f51\fs20\ql invention. Inventions developed solely by our scientists in connection with research collaborations are owned\plain\cf1\f51\fs20\ql exclusively by us. These collaborative agreements are non-exclusive and may be terminated with limited notice.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Research and Development Expenses\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are committed to redefining the treatment of certain cancers and rare diseases and have dedicated a\plain\cf1\f51\fs20\ql significant portion of our resources to our efforts on the discovery and development of our drug candidates.\~\~For the\plain\cf1\f51\fs20\ql years ended December\~31, 2017, 2016 and 2015, we spent approximately $50.7 million, $39.8 million, and $33.7\plain\cf1\f51\fs20\ql million, respectively, on research and development activities. We plan to continue to invest in research and\plain\cf1\f51\fs20\ql development. Accordingly, we anticipate that a significant portion of our operating expenses will continue to be\plain\cf1\f51\fs20\ql related to research and development in 2018 and beyond as we continue to advance our drug candidates into and\plain\cf1\f51\fs20\ql through clinical development.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Patents, Proprietary Rights and Trade Secrets\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our success depends in part on our ability to obtain and maintain proprietary protection for our drug\plain\cf1\f51\fs20\ql candidates, technology and know-how, to operate without infringing the proprietary rights of others and to prevent\plain\cf1\f51\fs20\ql others from infringing our proprietary rights. We use a variety of methods to seek to protect our proprietary\plain\cf1\f51\fs20\ql position, including filing U.S.\~and foreign patent applications related to our proprietary technology, inventions and\plain\cf1\f51\fs20\ql improvements that are important to the development of our business. We also rely on trade secrets, know-how,\plain\cf1\f51\fs20\ql continuing technological innovation, and in-licensing opportunities to develop and maintain our proprietary position.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have devoted and continue to devote a substantial amount of our resources into establishing intellectual\plain\sa132\cf1\f51\fs20\ql property protection for:
\par\pard\plain
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh405\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql Novel chemical entities that function as antagonists of TLR7, TLR8 or TLR9; and\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh405\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Composition and use of our nucleic acid chemistry compounds to treat and prevent a variety of diseases.\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of February 15, 2018, we owned about 49 U.S. patents and patent applications and about 136 patents and\plain\cf1\f51\fs20\ql patent applications throughout the rest of the world for our TLR-targeted immune modulation technologies.\par\pard\plain\sb528\cf1\f51\fs20\qc 11\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql These patents and patent applications include claims covering the chemical compositions of matter and methods of\plain\cf1\f51\fs20\ql use of our IMO compounds, such as IMO-8400, IMO-9200 and IMO-2125, as well as other compounds. These\plain\cf1\f51\fs20\ql patents expire at various dates ranging from 2023 to 2037. With respect to IMO-8400, we have five issued U.S.\plain\cf1\f51\fs20\ql patents that cover the chemical composition of matter of IMO-8400 and certain methods of its use that provide\plain\cf1\f51\fs20\ql exclusivity for IMO-8400 until at least 2031. With respect to IMO-9200, we have six issued U.S. patents and two\plain\cf1\f51\fs20\ql U.S. patent applications that cover the chemical composition for IMO-9200 and methods of its use that provide\plain\cf1\f51\fs20\ql exclusivity for IMO-9200 until at least 2034. With respect to IMO-2125, we have an issued U.S. patent that covers\plain\cf1\f51\fs20\ql the chemical composition of matter of IMO-2125 and methods of its use that will expire in 2025. We have pending\plain\cf1\f51\fs20\ql applications in the United States and outside of the United States that cover methods of treatment or use with\plain\cf1\f51\fs20\ql IMO-2125 with expiration dates of 2035 and 2037.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of February 15, 2018, we owned three issued U.S. patents, 25 issued foreign patents, five pending U.S.\plain\cf1\f51\fs20\ql patent applications and 12 foreign patent applications (including pending applications under the Patent Cooperation\plain\cf1\f51\fs20\ql Treaty, or PCT) related to our nucleic acid chemistry compounds and methods of their use. The issued patents\plain\cf1\f51\fs20\ql covering our nucleic acid chemistry technologies have an earliest statutory expiration date in 2030. One patent\plain\cf1\f51\fs20\ql family relating to targets for our nucleic acid chemistry compounds is in-licensed.\~\~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Because patent applications in the United States and many foreign jurisdictions are typically not published\plain\cf1\f51\fs20\ql until 18 months after filing, or in some cases not at all, and because publications of discoveries in the scientific\plain\cf1\f51\fs20\ql literature often lag behind actual discoveries, neither we nor our licensors can be certain that we or they were the\plain\cf1\f51\fs20\ql first to make the inventions claimed in issued patents or pending patent applications, or that we or they were the\plain\cf1\f51\fs20\ql first to file for protection of the inventions set forth in these patent applications.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Litigation may be necessary to defend against or assert claims of infringement, to enforce patents issued to\plain\cf1\f51\fs20\ql us, to protect trade secrets or know-how owned by us, or to determine the scope and validity of the proprietary\plain\cf1\f51\fs20\ql rights of others or to determine the appropriate term for an issued patent. In addition, the United States\~Patent and\plain\cf1\f51\fs20\ql Trademark Office, or USPTO, may declare interference proceedings to determine the priority of inventions with\plain\cf1\f51\fs20\ql respect to our patent applications or reexamination or reissue proceedings to determine if the scope of a patent\plain\cf1\f51\fs20\ql should be narrowed. Litigation or any of these other proceedings could result in substantial costs to and diversion of\plain\cf1\f51\fs20\ql effort by us, even if the eventual outcome is favorable to us, and could have a material adverse effect on our\plain\cf1\f51\fs20\ql business, financial condition and results of operations. These efforts by us may not be successful.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The term of individual patents depends upon the legal term for patents in the countries in which they are\plain\cf1\f51\fs20\ql obtained. In most countries, including the United States, the patent term is 20 years from the earliest filing date of a\plain\cf1\f51\fs20\ql non-provisional patent application. In the United States, a patent\u8217?s term may be lengthened by patent term\plain\cf1\f51\fs20\ql adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a\plain\cf1\f51\fs20\ql patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The term of a patent\plain\cf1\f51\fs20\ql that covers a drug, biological product or medical device approved pursuant to a pre-market approval may also be\plain\cf1\f51\fs20\ql eligible for patent term extension when FDA approval is granted, provided statutory and regulatory requirements are\plain\cf1\f51\fs20\ql met. The length of the patent term extension is related to the length of time the drug is under regulatory review\plain\cf1\f51\fs20\ql while the patent is in force. The Drug Price Competition and Patent Term Restoration Act of 1984, or the\plain\cf1\f51\fs20\ql Hatch-Waxman Act, permits a patent term extension of up to five years beyond the expiration date set for the\plain\cf1\f51\fs20\ql patent. Patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of\plain\cf1\f51\fs20\ql product approval, only one patent applicable to each regulatory review period may be granted an extension and only\plain\cf1\f51\fs20\ql those claims reading on the approved drug are extended. Similar provisions are available in Europe and other\plain\cf1\f51\fs20\ql foreign jurisdictions to extend the term of a patent that covers an approved drug.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We may rely, in some circumstances, on trade secrets and confidentiality agreements to protect our\plain\cf1\f51\fs20\ql technology. Although trade secrets are difficult to protect, wherever possible, we use confidential disclosure\plain\cf1\f51\fs20\ql agreements to protect the proprietary nature of our technology. We regularly implement confidentiality agreements\plain\cf1\f51\fs20\ql with our employees, consultants, scientific advisors, and other contractors and collaborators. However, there can be\plain\cf1\f51\fs20\ql no assurance that these agreements will not be breached, that we will have adequate remedies for any breach, or\plain\cf1\f51\fs20\ql that our trade secrets and/or proprietary information will not otherwise become known or be independently\plain\cf1\f51\fs20\ql discovered by competitors. To the extent that our employees, consultants or contractors use intellectual property\plain\cf1\f51\fs20\ql owned by others in their work for us, disputes may also arise as to the rights in related or resulting know-how and\plain\cf1\f51\fs20\ql inventions.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 12\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf11\f51\fs24\b\ql Manufacturing\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We do not currently own or operate manufacturing facilities for the production of clinical or commercial\plain\cf1\f51\fs20\ql quantities of any of our drug candidates. We currently rely and expect to continue to rely on other companies for\plain\cf1\f51\fs20\ql the manufacture of our drug candidates for preclinical and clinical development. We currently source our bulk drug\plain\cf1\f51\fs20\ql manufacturing requirements from a limited number of contract manufacturers through the issuance of work orders\plain\cf1\f51\fs20\ql on an as-needed basis. We depend and will continue to depend on our contract manufacturers to manufacture our\plain\cf1\f51\fs20\ql drug candidates in accordance with current Good Manufacturing Practices, or cGMP, regulations for use in clinical\plain\cf1\f51\fs20\ql trials. We will ultimately depend on contract manufacturers for the manufacture of our products for commercial\plain\cf1\f51\fs20\ql sale, if and when our drug candidates are approved. Contract manufacturers are subject to extensive governmental\plain\cf1\f51\fs20\ql regulation.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Under our collaborative agreement with GSK, GSK is responsible for manufacturing clinical drug candidates.\plain\cf1\f51\fs20\ql Under our collaborative agreement with Vivelix, Vivelix is responsible for manufacturing clinical drug candidates.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Competition\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense\plain\cf1\f51\fs20\ql competition and a strong emphasis on proprietary products. We are currently developing our TLR-targeted drug\plain\cf1\f51\fs20\ql candidates for use in our immuno-oncology program and in the treatment of certain rare diseases. IMO-2125, our\plain\cf1\f51\fs20\ql TLR agonist lead drug candidate, is being developed for the treatment by intra-tumoral injection of multiple\plain\cf1\f51\fs20\ql oncology indications in combination with checkpoint inhibitors. IMO-8400, our TLR antagonist lead drug\plain\cf1\f51\fs20\ql candidate, is being developed for the treatment of rare diseases with dermatomyositis as our lead clinical target. We\plain\cf1\f51\fs20\ql are also in collaboration with GSK for an undisclosed renal target and expect to continue to seek to enter into\plain\cf1\f51\fs20\ql additional collaborative alliances with pharmaceutical companies with respect to applications of our nucleic acid\plain\cf1\f51\fs20\ql chemistry technology program. For all of these disease areas, there are many other companies, public and private,\plain\cf1\f51\fs20\ql that are actively engaged in discovery, development, and commercializing products and technologies that may\plain\cf1\f51\fs20\ql compete with our drug candidates and programs, including TLR-targeted compounds as well as non-TLR-targeted\plain\cf1\f51\fs20\ql therapeutics.\~\~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are aware of other companies including Dynavax Technologies Corporation, Mologen AG, BioLineRx\plain\cf1\f51\fs20\ql Ltd., Innate Immunotherapeutics Ltd., VentiRx Pharmaceuticals Inc., Telormedix S.A., Gilead Sciences Inc.,\plain\cf1\f51\fs20\ql GlaxoSmithKline plc, AstraZeneca plc, Checkmate Pharmaceuticals, Inc., Hoffmann-La Roche Ltd. and\plain\cf1\f51\fs20\ql Nektar\~Therapeutics that are developing TLR agonists and antagonists for various indications, including oncology\plain\cf1\f51\fs20\ql and rare diseases.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql ILLUMINATE (IMO-2125) Clinical Development Program for Oncology Indications\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Immuno-oncology, which utilizes a patient\u8217?s own immune system to combat cancer, is currently an\plain\cf1\f51\fs20\ql active area of research for biotechnology and pharmaceutical companies. Interest in immuno-oncology is driven by\plain\cf1\f51\fs20\ql efficacy data in cancers with historically bleak outcomes and the potential to achieve a cure or functional cure for\plain\cf1\f51\fs20\ql some patients. As such, we expect that our efforts in this field will be competitive with a wide variety of different\plain\cf1\f51\fs20\ql approaches. Any one of these competitive approaches may result in the development of novel technologies that are\plain\cf1\f51\fs20\ql more effective, safer or less costly than any that we are developing. In addition, Dynavax is conducting a Phase 1/2\plain\cf1\f51\fs20\ql clinical trial of its proprietary investigational TLR9 agonist, intra-tumoral SD-101, in combination with checkpoint\plain\cf1\f51\fs20\ql inhibitors, and OncoSec Medical Incorporated is conducting a Phase 2 clinical trial of intra-tumoral pIL-12 in\plain\cf1\f51\fs20\ql metastatic melanoma in combination with checkpoint inhibitors.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql PIONEER (IMO-8400) Trial in Dermatomyositis\~\~\~\~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Many of the drug development programs in dermatomyositis are focusing on expanding the use of drugs\plain\cf1\f51\fs20\ql approved in different indications through investigator sponsored studies such as the ongoing studies of the\plain\cf1\f51\fs20\ql monoclonal antibodies, belimumab and tocilizumab. In addition, Pfizer is developing PF06823859 (interferon beta\plain\cf1\f51\fs20\ql inhibitor) for the treatment of dermatomyositis which is in a Phase 2a trial and Corbus Pharmaceuticals has reported\plain\cf1\f51\fs20\ql positive results with lenabasum (synthetic oral endocannabinoid-mimetic drug) for the treatment of dermatomyositis\plain\cf1\f51\fs20\ql in a Phase 2b trial.\~\~We are not aware of other new chemical or molecular entities being developed for the treatment\plain\cf1\f51\fs20\ql of dermatomyositis.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 13\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\i\ql Nucleic Acid Chemistry Technology to Target RNA\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are developing nucleic acid chemistry drug candidates that we have created using our proprietary\plain\cf1\f51\fs20\ql technology to inhibit the production of disease-associated proteins by targeting RNA. We also face competition\plain\cf1\f51\fs20\ql from other companies working to develop novel drugs using technologies that may compete with our nucleic acid\plain\cf1\f51\fs20\ql chemistry technology. We are aware of multiple companies that are developing technologies that use\plain\cf1\f51\fs20\ql oligonucleotide-based compounds to inhibit the production of disease associated proteins. These technologies\plain\cf1\f51\fs20\ql include, but are not limited to, antisense technology as well as RNAi. In the field of antisense technologies, we\plain\cf1\f51\fs20\ql compete with multiple companies, including Ionis Pharmaceuticals, Inc., or Ionis, and its strategic partners, as well\plain\cf1\f51\fs20\ql as WAVE Life Sciences and its strategic partner. Ionis is currently marketing an antisense drug, Kynamro, and has\plain\cf1\f51\fs20\ql submitted via Akcea both an NDA and marketing authorization application for Volanesorsen (targets APOC3) to the\plain\cf1\f51\fs20\ql FDA and European regulatory agencies. Ionis has over two dozen antisense drug candidates in clinical trials. Biogen\plain\cf1\f51\fs20\ql recently received FDA approval for its antisense drug Spinraza for spinal muscular atrophy.\~\~In the field of RNAi,\plain\cf1\f51\fs20\ql we compete with Alnylam, Dicerna, Miragen, and their respective partners. Any of the competing companies may\plain\cf1\f51\fs20\ql develop gene-silencing technologies more rapidly and more effectively than us, and\~antisense technology and RNAi\plain\cf1\f51\fs20\ql may become the preferred technology for drugs that target RNA in order to inhibit the production of\plain\cf1\f51\fs20\ql disease-associated proteins.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Some of these potentially competitive products have been in development or commercialized for years, in\plain\cf1\f51\fs20\ql some cases by large, well established pharmaceutical companies. Many of the marketed products have been\plain\cf1\f51\fs20\ql accepted by the medical community, patients, and third-party payors. Our ability to compete may be affected by the\plain\cf1\f51\fs20\ql previous adoption of such products by the medical community, patients, and third-party payors. Additionally, in\plain\cf1\f51\fs20\ql some instances, insurers and other third-party payors seek to encourage the use of generic products, which makes\plain\cf1\f51\fs20\ql branded products, such as is planned for our drug candidates upon commercialization, potentially less attractive,\plain\cf1\f51\fs20\ql from a cost perspective, to buyers.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We recognize that other companies, including large pharmaceutical companies, may be developing or have\plain\cf1\f51\fs20\ql plans to develop products and technologies that may compete with ours. Many of our competitors have substantially\plain\cf1\f51\fs20\ql greater financial, technical, and human resources than we have. In addition, many of our competitors have\plain\cf1\f51\fs20\ql significantly greater experience than we have in undertaking preclinical studies and human clinical trials of new\plain\cf1\f51\fs20\ql pharmaceutical products, obtaining FDA and other regulatory approvals of products for use in health care and\plain\cf1\f51\fs20\ql manufacturing, and marketing and selling approved products. Our competitors may discover, develop or\plain\cf1\f51\fs20\ql commercialize products or other novel technologies that are more effective, safer or less costly than any that we are\plain\cf1\f51\fs20\ql developing. Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than\plain\cf1\f51\fs20\ql we may obtain approval for ours.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We anticipate that the competition with our drug candidates and technologies will be based on a number of\plain\cf1\f51\fs20\ql factors including product efficacy, safety, availability, and price. The timing of market introduction of our drug\plain\cf1\f51\fs20\ql candidates and competitive products will also affect competition among products. We expect the relative speed with\plain\cf1\f51\fs20\ql which we can develop products, complete the clinical trials and approval processes, and supply commercial\plain\cf1\f51\fs20\ql quantities of the products to the market to be important competitive factors. Our competitive position will also\plain\cf1\f51\fs20\ql depend upon our ability to attract and retain qualified personnel, to obtain patent protection or otherwise develop\plain\cf1\f51\fs20\ql proprietary products or processes, protect our intellectual property, and to secure sufficient capital resources for the\plain\cf1\f51\fs20\ql period between technological conception and commercial sales.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 14\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf11\f51\fs24\b\ql Government Regulation\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Government authorities in the United States, at the federal, state and local level, and in other countries and\plain\cf1\f51\fs20\ql jurisdictions, including the European Union, extensively regulate, among other things, the research, development,\plain\cf1\f51\fs20\ql testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion,\plain\cf1\f51\fs20\ql distribution, marketing, pricing, post-approval monitoring and reporting, and import and export of pharmaceutical\plain\cf1\f51\fs20\ql products. The processes for obtaining regulatory approvals in the United States and in foreign countries and\plain\cf1\f51\fs20\ql jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory\plain\cf1\f51\fs20\ql authorities, require the expenditure of substantial time and financial resources.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Review and Approval of Drugs in the United States\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA,\plain\cf1\f51\fs20\ql and associated implementing regulations. The failure to comply with the FDCA and other applicable U.S.\plain\cf1\f51\fs20\ql requirements at any time during the product development process, approval process or after approval may subject an\plain\cf1\f51\fs20\ql applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to\plain\cf1\f51\fs20\ql approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters\plain\cf1\f51\fs20\ql and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution,\plain\cf1\f51\fs20\ql injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal\plain\cf1\f51\fs20\ql investigations and penalties brought by the FDA and the Department of Justice, or DOJ, or other governmental\plain\cf1\f51\fs20\ql entities, including state agencies.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql An applicant seeking approval to market and distribute a new drug product in the United States must\plain\cf1\f51\fs20\ql typically undertake the following:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh495\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh495\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 15\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\i\ql Preclinical Studies\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product\plain\cf1\f51\fs20\ql candidate enters the preclinical testing stage. Preclinical studies include laboratory evaluation of the purity and\plain\cf1\f51\fs20\ql stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug\plain\cf1\f51\fs20\ql product, as well as in vitro and animal studies to assess the safety and activity of the drug for initial testing in\plain\cf1\f51\fs20\ql humans and to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal\plain\cf1\f51\fs20\ql regulations and requirements, including GLP regulations. The results of the preclinical tests, together with\plain\cf1\f51\fs20\ql manufacturing information, analytical data, any available clinical data or literature and plans for clinical studies,\plain\cf1\f51\fs20\ql among other things, are submitted to the FDA as part of an IND. Additional preclinical testing, such as animal tests\plain\cf1\f51\fs20\ql of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Human Clinical Studies in Support of an NDA\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Clinical trials involve the administration of the investigational product to human subjects under the\plain\cf1\f51\fs20\ql supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the\plain\cf1\f51\fs20\ql requirement that all research subjects provide their informed consent in writing before their participation in any\plain\cf1\f51\fs20\ql clinical trial. Clinical trials are conducted under written study protocols detailing, among other things, the objectives\plain\cf1\f51\fs20\ql of the study, inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness\plain\cf1\f51\fs20\ql criteria to be evaluated. A protocol for each clinical trial and any subsequent protocol amendments must be\plain\cf1\f51\fs20\ql submitted to the FDA as part of the IND. An IND is an exemption from the FDCA that allows an unapproved\plain\cf1\f51\fs20\ql product candidate to be shipped in interstate commerce for use in an investigational clinical trial and a request for\plain\cf1\f51\fs20\ql FDA authorization to administer such investigational product to humans. An IND automatically becomes effective\plain\cf1\f51\fs20\ql 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to a\plain\cf1\f51\fs20\ql proposed clinical trial and places the trial on clinical hold or partial clinical hold. In such a case, the IND sponsor\plain\cf1\f51\fs20\ql and the FDA must resolve any outstanding concerns before the clinical trial can begin.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Typically, the FDA will require one IND for early development studies where the sponsor is uncertain of the\plain\cf1\f51\fs20\ql indication or dosage form of the proposed product, where the drug is being developed for closely related indications\plain\cf1\f51\fs20\ql within a single review division at FDA, or where there are multiple closely-related routes of administration using\plain\cf1\f51\fs20\ql the same dosage formulation. On the other hand, multiple INDs may be required where there are two or more\plain\cf1\f51\fs20\ql unrelated conditions being developed or where multiple dosage forms are being extensively investigated or where\plain\cf1\f51\fs20\ql multiple routes of administration are being evaluated.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition to the foregoing IND requirements, an IRB representing each institution participating in the\plain\cf1\f51\fs20\ql clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the\plain\cf1\f51\fs20\ql IRB must conduct continuing review and reapprove the study at least annually. The IRB must review and approve,\plain\cf1\f51\fs20\ql among other things, the study protocol and informed consent information to be provided to study subjects. An IRB\plain\cf1\f51\fs20\ql must operate in compliance with FDA regulations. Information about certain clinical trials must be submitted within\plain\cf1\f51\fs20\ql specific timeframes to the National Institutes of Health for public dissemination on their ClinicalTrials.gov website.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Additionally, some trials are overseen by an independent group of qualified experts organized by the trial\plain\cf1\f51\fs20\ql sponsor, known as a data safety monitoring board or committee, or DSMB. This group provides recommendations\plain\cf1\f51\fs20\ql as to whether or not a trial should move forward at designated check points based on access that only the group\plain\cf1\f51\fs20\ql maintains to available data from the study. Suspension or termination of development during any phase of clinical\plain\cf1\f51\fs20\ql trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk.\plain\cf1\f51\fs20\ql Other reasons for suspension or termination may be made by us based on evolving business objectives and/or\plain\cf1\f51\fs20\ql competitive climate.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Phase 1:\plain\cf1\f51\fs20\ql \~\~\~\~The drug is initially introduced into healthy human subjects or patients with the target disease\plain\cf1\f51\fs20\ql (e.g. cancer) or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and,\plain\cf1\f51\fs20\ql if possible, to gain an early indication of its effectiveness and to determine optimal dosage.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Phase 2:\plain\cf1\f51\fs20\ql \~\~\~\~The drug is administered to a limited patient population to identify possible adverse effects and\plain\cf1\f51\fs20\ql safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine\plain\cf1\f51\fs20\ql dosage tolerance and optimal dosage.\par\pard\plain\sb528\cf1\f51\fs20\qc 16\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Phase 3:\plain\cf1\f51\fs20\ql \~\~\~\~The drug is administered to an expanded patient population, generally at geographically dispersed\plain\cf1\f51\fs20\ql clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and\plain\cf1\f51\fs20\ql safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide\plain\cf1\f51\fs20\ql adequate information for the labeling of the product.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and\plain\cf1\f51\fs20\ql more frequently if serious adverse events occur. In addition, IND safety reports must be submitted to the FDA for\plain\cf1\f51\fs20\ql any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or\plain\cf1\f51\fs20\ql in vitro testing that suggest a significant risk in humans exposed to the drug; and any clinically important increase\plain\cf1\f51\fs20\ql in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. Phase 1,\plain\cf1\f51\fs20\ql Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.\plain\cf1\f51\fs20\ql Furthermore, the FDA, the sponsor or the data monitoring committee for a clinical trial may suspend or terminate\plain\cf1\f51\fs20\ql the clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to\plain\cf1\f51\fs20\ql an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution,\plain\cf1\f51\fs20\ql or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB\u8217?s\plain\cf1\f51\fs20\ql requirements or if the drug has been associated with unexpected serious harm to patients. The FDA will typically\plain\cf1\f51\fs20\ql inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Section\~505(b)(2) NDAs\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql NDAs for most new drug products are based on two full clinical studies which must contain substantial\plain\cf1\f51\fs20\ql evidence of the safety and efficacy of the proposed new product. These applications are submitted under\plain\cf1\f51\fs20\ql Section\~505(b)(1) of the FDCA. The FDA is, however, authorized to approve an alternative type of NDA under\plain\cf1\f51\fs20\ql Section\~505(b)(2) of the FDCA. This type of application allows the applicant to rely, in part, on the FDA\u8217?s\plain\cf1\f51\fs20\ql previous findings of safety and efficacy for a similar product, or published literature. Specifically, Section\~505(b)(2)\plain\cf1\f51\fs20\ql applies to NDAs for a drug for which the investigations made to show whether or not the drug is safe for use and\plain\cf1\f51\fs20\ql effective in use and relied upon by the applicant for approval of the application \u8220?were not conducted by or\plain\cf1\f51\fs20\ql for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for\plain\cf1\f51\fs20\ql whom the investigations were conducted.\u8221?\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Thus, Section\~505(b)(2) authorizes the FDA to approve an NDA based on safety and effectiveness data that\plain\cf1\f51\fs20\ql were not developed by the applicant. NDAs filed under Section\~505(b)(2) may provide an alternate and potentially\plain\cf1\f51\fs20\ql more expeditious pathway to FDA approval for new or improved formulations or new uses of previously approved\plain\cf1\f51\fs20\ql products. If the Section\~505(b)(2) applicant can establish that reliance on the FDA\u8217?s previous approval is\plain\cf1\f51\fs20\ql scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies of\plain\cf1\f51\fs20\ql the new product. The FDA may also require companies to perform additional studies or measurements to support\plain\cf1\f51\fs20\ql the change from the approved product. The FDA may then approve the new drug candidate for all or some of the\plain\cf1\f51\fs20\ql label indications for which the referenced product has been approved, as well as for any new indication sought by\plain\cf1\f51\fs20\ql the Section\~505(b)(2) applicant.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Submission of an NDA to the FDA\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Assuming successful completion of required clinical testing and other requirements, the results of the\plain\cf1\f51\fs20\ql preclinical and clinical studies, together with detailed information relating to the product\u8217?s chemistry,\plain\cf1\f51\fs20\ql manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA\plain\cf1\f51\fs20\ql requesting approval to market the drug product for one or more indications. Under federal law, the submission of\plain\cf1\f51\fs20\ql most NDAs is subject to an application user fee, which for federal fiscal year 2018 is $2,421,495 for an application\plain\cf1\f51\fs20\ql requiring clinical data. The sponsor of an approved NDA is also subject to an annual program fee, which for fiscal\plain\cf1\f51\fs20\ql year 2018 is $304,162. Exceptions or waivers for these fees exist for a small company (fewer than 500 employees,\plain\cf1\f51\fs20\ql including employees and affiliates) satisfying certain requirements and products with orphan drug designation for a\plain\cf1\f51\fs20\ql particular indication are not subject to a fee provided there are no other intended uses in the NDA.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA conducts a preliminary review of an NDA within 60 calendar days of its receipt and strives to\plain\cf1\f51\fs20\ql inform the sponsor by the 74th day after the FDA\u8217?s receipt of the submission to determine whether the\plain\cf1\f51\fs20\ql application is sufficiently complete to permit substantive review. The FDA may request additional information rather\plain\cf1\f51\fs20\ql than accept an NDA for filing. In this event, the application must be resubmitted with the additional information.\plain\cf1\f51\fs20\ql The\par\pard\plain\sb528\cf1\f51\fs20\qc 17\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is\plain\cf1\f51\fs20\ql accepted for filing, the FDA begins an in-depth substantive review. \~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA has agreed to specified performance goals in the review process of NDAs. Under the agreement,\plain\cf1\f51\fs20\ql 90% of applications seeking approval of New Molecular Entities, or NMEs, are meant to be reviewed within ten\plain\cf1\f51\fs20\ql months from the date on which the FDA accepts the NDA for filing, and 90% of applications for NMEs that have\plain\cf1\f51\fs20\ql been designated for \u8220?priority review\u8221? are meant to be reviewed within six months of the filing date.\plain\cf1\f51\fs20\ql For applications seeking approval of drugs that are not NMEs, the ten-month and six-month review periods run\plain\cf1\f51\fs20\ql from the date that the FDA receives the application.\~\~The review process may be extended by the FDA for three\plain\cf1\f51\fs20\ql additional months to consider new information or clarification provided by the applicant to address an outstanding\plain\cf1\f51\fs20\ql deficiency identified by the FDA following the original submission.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or\plain\cf1\f51\fs20\ql will be manufactured. These pre-approval inspections cover all facilities associated with an NDA submission,\plain\cf1\f51\fs20\ql including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product\plain\cf1\f51\fs20\ql manufacturing, and control testing laboratories. The FDA will not approve an application unless it determines that\plain\cf1\f51\fs20\ql the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure\plain\cf1\f51\fs20\ql consistent production of the product within required specifications. Additionally, before approving an NDA, the\plain\cf1\f51\fs20\ql FDA will typically inspect one or more clinical sites to assure compliance with GCP.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, as a condition of approval, the FDA may require an applicant to develop a REMS.\~REMS use\plain\cf1\f51\fs20\ql risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the\plain\cf1\f51\fs20\ql potential risks.\~To determine whether a REMS is needed, the FDA will consider the size of the population likely to\plain\cf1\f51\fs20\ql use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment,\plain\cf1\f51\fs20\ql seriousness of known or potential adverse events, and whether the product is a new molecular entity.\~REMS can\plain\cf1\f51\fs20\ql include medication guides, physician communication plans for healthcare professionals, and elements to assure safe\plain\cf1\f51\fs20\ql use, or ETASU. ETASU may include, but are not limited to, special training or certification for prescribing or\plain\cf1\f51\fs20\ql dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.\~The\plain\cf1\f51\fs20\ql FDA may require a REMS before approval or post-approval if it becomes aware of a serious risk associated with\plain\cf1\f51\fs20\ql use of the product.\~The requirement for a REMS can materially affect the potential market and profitability of a\plain\cf1\f51\fs20\ql product.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA is required to refer an application for a novel drug to an advisory committee or explain why such\plain\cf1\f51\fs20\ql referral was not made. Typically, an advisory committee is a panel of independent experts, including clinicians and\plain\cf1\f51\fs20\ql other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should\plain\cf1\f51\fs20\ql be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee,\plain\cf1\f51\fs20\ql but it considers such recommendations carefully when making decisions.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Fast Track, Breakthrough Therapy and Priority Review Designations\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA is authorized to designate certain products for expedited review if they are intended to address an\plain\cf1\f51\fs20\ql unmet medical need in the treatment of a serious or life-threatening disease or condition. These programs are fast\plain\cf1\f51\fs20\ql track designation, breakthrough therapy designation and priority review designation.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Specifically, the FDA may designate a product for fast track review if it is intended, whether alone or in\plain\cf1\f51\fs20\ql combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition,\plain\cf1\f51\fs20\ql and it demonstrates the potential to address unmet medical needs for such a disease or condition. For fast track\plain\cf1\f51\fs20\ql products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a\plain\cf1\f51\fs20\ql fast track product\u8217?s NDA before the application is complete. This rolling review may be available if the FDA\plain\cf1\f51\fs20\ql determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be\plain\cf1\f51\fs20\ql effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the\plain\cf1\f51\fs20\ql remaining information and the sponsor must pay applicable user fees. However, the FDA\u8217?s time period goal\plain\cf1\f51\fs20\ql for reviewing a fast track application does not begin until the last section of the NDA is submitted. In addition, the\plain\cf1\f51\fs20\ql fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer\plain\cf1\f51\fs20\ql supported by data emerging in the clinical trial process.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Second, in 2012, Congress enacted the Food and Drug Administration Safety and Innovation Act, or\plain\cf1\f51\fs20\ql FDASIA. This law established a new regulatory scheme allowing for expedited review of products designated as\plain\cf1\f51\fs20\ql \u8220?breakthrough therapies.\u8221? A product may be designated as a breakthrough therapy if it is intended,\plain\cf1\f51\fs20\ql either alone or\par\pard\plain\sb528\cf1\f51\fs20\qc 18\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and\plain\cf1\f51\fs20\ql preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing\plain\cf1\f51\fs20\ql therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in\plain\cf1\f51\fs20\ql clinical development. The FDA may take certain actions with respect to breakthrough therapies, including holding\plain\cf1\f51\fs20\ql meetings with the sponsor throughout the development process; providing timely advice to the product sponsor\plain\cf1\f51\fs20\ql regarding development and approval; involving more senior staff in the review process; assigning a\plain\cf1\f51\fs20\ql cross-disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient\plain\cf1\f51\fs20\ql manner.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Third, the FDA may designate a product for priority review if it is a drug that treats a serious condition and,\plain\cf1\f51\fs20\ql if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a\plain\cf1\f51\fs20\ql case-by-case basis, whether the proposed drug represents a significant improvement when compared with other\plain\cf1\f51\fs20\ql available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the\plain\cf1\f51\fs20\ql treatment of a condition, elimination or substantial reduction of a treatment-limiting drug reaction, documented\plain\cf1\f51\fs20\ql enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and\plain\cf1\f51\fs20\ql effectiveness in a new subpopulation. A priority designation is intended to direct overall attention and resources to\plain\cf1\f51\fs20\ql the evaluation of such applications, and to shorten the FDA\u8217?s goal for taking action on a marketing\plain\cf1\f51\fs20\ql application from ten months to six months.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Accelerated Approval Pathway\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA may grant accelerated approval to a drug for a serious or life-threatening condition that provides\plain\cf1\f51\fs20\ql meaningful therapeutic advantage to patients over existing treatments based upon a determination that the drug has\plain\cf1\f51\fs20\ql an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant\plain\cf1\f51\fs20\ql accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that\plain\cf1\f51\fs20\ql can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely\plain\cf1\f51\fs20\ql to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity,\plain\cf1\f51\fs20\ql rarity, or prevalence of the condition and the availability or lack of alternative treatments. Drugs granted accelerated\plain\cf1\f51\fs20\ql approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement,\plain\cf1\f51\fs20\ql radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a\plain\cf1\f51\fs20\ql measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical\plain\cf1\f51\fs20\ql endpoints. An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably\plain\cf1\f51\fs20\ql likely to predict the clinical benefit of a drug, such as an effect on IMM. The FDA has limited experience with\plain\cf1\f51\fs20\ql accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may\plain\cf1\f51\fs20\ql support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit\plain\cf1\f51\fs20\ql and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to\plain\cf1\f51\fs20\ql predict the ultimate clinical benefit of a drug.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The accelerated approval pathway is most often used in settings in which the course of a disease is long and\plain\cf1\f51\fs20\ql an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the\plain\cf1\f51\fs20\ql surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in\plain\cf1\f51\fs20\ql the development and approval of drugs for treatment of a variety of cancers in which the goal of therapy is\plain\cf1\f51\fs20\ql generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy\plain\cf1\f51\fs20\ql and sometimes large trials to demonstrate a clinical or survival benefit.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The accelerated approval pathway is usually contingent on a sponsor\u8217?s agreement to conduct, in a\plain\cf1\f51\fs20\ql diligent manner, additional post-approval confirmatory studies to verify and describe the drug\u8217?s clinical\plain\cf1\f51\fs20\ql benefit.\~As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance\plain\cf1\f51\fs20\ql requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the\plain\cf1\f51\fs20\ql clinical endpoint. Failure to conduct required post-approval studies, or confirm a clinical benefit during\plain\cf1\f51\fs20\ql post-marketing studies, would allow the FDA to withdraw the drug from the market on an expedited basis. All\plain\cf1\f51\fs20\ql promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the\plain\cf1\f51\fs20\ql FDA.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 19\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\i\ql The FDA\u8217?s Decision on an NDA\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql On the basis of the FDA\u8217?s evaluation of the NDA and accompanying information, including the results\plain\cf1\f51\fs20\ql of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.\plain\cf1\f51\fs20\ql An approval letter authorizes commercial marketing of the product with specific prescribing information for specific\plain\cf1\f51\fs20\ql indications. A complete response letter generally outlines the deficiencies in the submission and may require\plain\cf1\f51\fs20\ql substantial additional testing or information in order for the FDA to reconsider the application. If and when those\plain\cf1\f51\fs20\ql deficiencies have been addressed to the FDA\u8217?s satisfaction in a resubmission of the NDA, the FDA will\plain\cf1\f51\fs20\ql issue an approval letter. The FDA has committed to reviewing such resubmissions in two or six months depending\plain\cf1\f51\fs20\ql on the type of information included. Even with submission of this additional information, the FDA ultimately may\plain\cf1\f51\fs20\ql decide that the application does not satisfy the regulatory criteria for approval.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If the FDA approves a product, it may limit the approved indications for use for the product, require that\plain\cf1\f51\fs20\ql contraindications, warnings or precautions be included in the product labeling, require that post-approval studies,\plain\cf1\f51\fs20\ql including Phase 4 clinical trials, be conducted to further assess the drug\u8217?s safety after approval, require\plain\cf1\f51\fs20\ql testing and surveillance programs to monitor the product after commercialization, or impose other conditions,\plain\cf1\f51\fs20\ql including distribution restrictions or other risk management mechanisms, including REMS, which can materially\plain\cf1\f51\fs20\ql affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a\plain\cf1\f51\fs20\ql product based on the results of post-market studies or surveillance programs. After approval, many types of changes\plain\cf1\f51\fs20\ql to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are\plain\cf1\f51\fs20\ql subject to further testing requirements and FDA review and approval.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql FDA Regulation of Companion Diagnostics\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql If safe and effective use of a therapeutic depends on an in vitro diagnostic, then the FDA generally will require\plain\cf1\f51\fs20\ql approval or clearance of that diagnostic, known as a companion diagnostic, at the same time that the FDA approves\plain\cf1\f51\fs20\ql the therapeutic product. In August 2014, the FDA issued final guidance clarifying the requirements that will apply\plain\cf1\f51\fs20\ql to approval of therapeutic products and in vitro companion diagnostics. According to the guidance, for novel drugs,\plain\cf1\f51\fs20\ql a companion diagnostic device and its corresponding therapeutic should be approved or cleared contemporaneously\plain\cf1\f51\fs20\ql by the FDA for the use indicated in the therapeutic product\u8217?s labeling. In July 2016, the FDA issued a draft\plain\cf1\f51\fs20\ql guidance intended to assist sponsors of the drug therapeutic and in vitro companion diagnostic device on issues\plain\cf1\f51\fs20\ql related to co-development of the products.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA previously has required\plain\cf1\f51\fs20\i\ql in vitro\plain\cf1\f51\fs20\ql companion diagnostics intended to select the patients who will\plain\cf1\f51\fs20\ql respond to the drug candidate to obtain pre-market approval, or PMA, simultaneously with approval of the drug.\plain\cf1\f51\fs20\ql The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the\plain\cf1\f51\fs20\ql FDA, can take several years or longer. It involves a rigorous premarket review during which the applicant must\plain\cf1\f51\fs20\ql prepare and provide the FDA with reasonable assurance of the device\u8217?s safety and effectiveness and\plain\cf1\f51\fs20\ql information about the device and its components regarding, among other things, device design, manufacturing and\plain\cf1\f51\fs20\ql labeling.\~\~PMA applications are subject to fees for medical device product review; for federal fiscal year 2018, the\plain\cf1\f51\fs20\ql standard fee for review of a PMA is $310,764 and the small business fee is $77,691.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql After a device is placed on the market, it remains subject to significant regulatory requirements. Medical\plain\cf1\f51\fs20\ql devices may be marketed only for the uses and indications for which they are cleared or approved. Device\plain\cf1\f51\fs20\ql manufacturers must also establish registration and device listings with the FDA. A medical device\plain\cf1\f51\fs20\ql manufacturer\u8217?s manufacturing processes and those of its suppliers are required to comply with the applicable\plain\cf1\f51\fs20\ql portions of the QSR, which cover the methods and documentation of the design, testing, production, processes,\plain\cf1\f51\fs20\ql controls, quality assurance, labeling, packaging and shipping of medical devices. Domestic facility records and\plain\cf1\f51\fs20\ql manufacturing processes are subject to periodic unscheduled inspections by the FDA. The FDA also may inspect\plain\cf1\f51\fs20\ql foreign facilities that export products to the U.S.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Post-Approval Requirements\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing\plain\cf1\f51\fs20\ql regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting,\plain\cf1\f51\fs20\ql product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.\plain\cf1\f51\fs20\ql After approval, most changes to the approved product, such as adding new indications or other labeling claims, are\plain\cf1\f51\fs20\ql subject to prior FDA review and approval. There also are continuing, annual user fee requirements for\par\pard\plain\sb528\cf1\f51\fs20\qc 20\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql any marketed products and the establishments at which such products are manufactured, as well as new application\plain\cf1\f51\fs20\ql fees for supplemental applications with clinical data.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved\plain\cf1\f51\fs20\ql drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic\plain\cf1\f51\fs20\ql unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. Changes to\plain\cf1\f51\fs20\ql the manufacturing process are strictly regulated and often require prior FDA approval before being implemented.\plain\cf1\f51\fs20\ql FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and\plain\cf1\f51\fs20\ql documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to\plain\cf1\f51\fs20\ql use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and\plain\cf1\f51\fs20\ql quality control to maintain cGMP compliance.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements\plain\cf1\f51\fs20\ql and standards is not maintained or if problems occur after the product reaches the market. Later discovery of\plain\cf1\f51\fs20\ql previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or\plain\cf1\f51\fs20\ql with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the\plain\cf1\f51\fs20\ql approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new\plain\cf1\f51\fs20\ql safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences\plain\cf1\f51\fs20\ql include, among other things:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql injunctions or the imposition of civil or criminal penalties.\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products\plain\cf1\f51\fs20\ql placed on the market. This regulation includes, among other things, standards and regulations for\plain\cf1\f51\fs20\ql direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and\plain\cf1\f51\fs20\ql educational activities, and promotional activities involving the Internet and social media. Promotional claims about a\plain\cf1\f51\fs20\ql drug\u8217?s safety or effectiveness are prohibited before the drug is approved. After approval, a drug product\plain\cf1\f51\fs20\ql generally may not be promoted for uses that are not approved by the FDA, as reflected in the product\u8217?s\plain\cf1\f51\fs20\ql prescribing information. In the United States, health care professionals are generally permitted to prescribe drugs for\plain\cf1\f51\fs20\ql such uses not described in the drug\u8217?s labeling, known as off-label uses, because the FDA does not regulate\plain\cf1\f51\fs20\ql the practice of medicine. However, FDA regulations impose rigorous restrictions on manufacturers\u8217?\plain\cf1\f51\fs20\ql communications, prohibiting the promotion of off-label uses. It may be permissible, under very specific, narrow\plain\cf1\f51\fs20\ql conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label\plain\cf1\f51\fs20\ql information, such as distributing scientific or medical journal information.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If a company is found to have promoted off-label uses, it may become subject to adverse public relations\plain\cf1\f51\fs20\ql and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector\plain\cf1\f51\fs20\ql General of the Department of Health and Human Services, as well as state authorities. This could subject a\plain\cf1\f51\fs20\ql company to a range of penalties that could have a significant commercial impact, including civil and criminal fines\plain\cf1\f51\fs20\ql and agreements that materially restrict the manner in which a company promotes or distributes drug products. The\plain\cf1\f51\fs20\ql federal government has levied large civil and criminal fines against companies for alleged improper promotion, and\plain\cf1\f51\fs20\ql has also requested that companies enter into consent decrees or permanent injunctions under which specified\plain\cf1\f51\fs20\ql promotional conduct is changed or curtailed.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug\plain\cf1\f51\fs20\ql Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or\plain\cf1\f51\fs20\ql DSCA, which regulate the distribution and tracing of prescription drug samples at the federal level, and set\plain\cf1\f51\fs20\ql minimum standards for the regulation of drug distributors by the states. The PDMA, its implementing regulations\plain\cf1\f51\fs20\ql and state\par\pard\plain\sb528\cf1\f51\fs20\qc 21\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql laws limit the distribution of prescription pharmaceutical product samples and the DSCA imposes requirements to\plain\cf1\f51\fs20\ql ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the\plain\cf1\f51\fs20\ql market.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Abbreviated New Drug Applications for Generic Drugs\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to\plain\cf1\f51\fs20\ql approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the\plain\cf1\f51\fs20\ql statute. To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or\plain\cf1\f51\fs20\ql ANDA, to the agency. In support of such applications, a generic manufacturer may rely on the preclinical and\plain\cf1\f51\fs20\ql clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference\plain\cf1\f51\fs20\ql listed drug, or RLD.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to\plain\cf1\f51\fs20\ql the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the\plain\cf1\f51\fs20\ql drug. At the same time, the FDA must also determine that the generic drug is \u8220?bioequivalent\u8221? to the\plain\cf1\f51\fs20\ql innovator drug. Under the statute, a generic drug is bioequivalent to a RLD if \u8220?the rate and extent of\plain\cf1\f51\fs20\ql absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed\plain\cf1\f51\fs20\ql drug.\u8221?\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Upon approval of an ANDA, the FDA indicates whether the generic product is \u8220?therapeutically\plain\cf1\f51\fs20\ql equivalent\u8221? to the RLD in its publication \u8220?Approved Drug Products with Therapeutic Equivalence\plain\cf1\f51\fs20\ql Evaluations,\u8221? also referred to as the \u8220?Orange Book.\u8221? Physicians and pharmacists consider a\plain\cf1\f51\fs20\ql therapeutic equivalent generic drug to be fully substitutable for the RLD. In addition, by operation of certain state\plain\cf1\f51\fs20\ql laws and numerous health insurance programs, the FDA\u8217?s designation of therapeutic equivalence often results\plain\cf1\f51\fs20\ql in substitution of the generic drug without the knowledge or consent of either the prescribing physician or patient.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Under the Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of\plain\cf1\f51\fs20\ql non-patent exclusivity for the RLD has expired. The FDCA provides a period of five years of non-patent data\plain\cf1\f51\fs20\ql exclusivity for a new drug containing a new chemical entity. For the purposes of this provision, a new chemical\plain\cf1\f51\fs20\ql entity, or NCE, is a drug that contains no active moiety that has previously been approved by the FDA in any other\plain\cf1\f51\fs20\ql NDA. An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the\plain\cf1\f51\fs20\ql drug substance. In cases where such exclusivity has been granted, an ANDA may not be filed with the FDA until\plain\cf1\f51\fs20\ql the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the\plain\cf1\f51\fs20\ql applicant may submit its application four years following the original product approval. The FDCA also provides\plain\cf1\f51\fs20\ql for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations,\plain\cf1\f51\fs20\ql other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to\plain\cf1\f51\fs20\ql the approval of the application. This three-year exclusivity period often protects changes to a previously approved\plain\cf1\f51\fs20\ql drug product, such as a new dosage form, route of administration, combination or indication.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug\plain\cf1\f51\fs20\ql application within eight (8) months for a drug that has three (3) or fewer approved drugs listed in the Orange Book\plain\cf1\f51\fs20\ql and is no longer protected by any patent or regulatory exclusivities, or is on the FDA\u8217?s drug shortage list.\plain\cf1\f51\fs20\ql The new legislation also authorizes FDA to expedite review of \u8216?\u8216?competitor generic\plain\cf1\f51\fs20\ql therapies\u8217?\u8217? or drugs with inadequate generic competition, including holding meetings with or providing\plain\cf1\f51\fs20\ql advice to the drug sponsor prior to submission of the application.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Hatch-Waxman Patent Certification and the 30-Month Stay\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each\plain\cf1\f51\fs20\ql patent with claims that cover the applicant\u8217?s product or an approved method of using the product. Each of\plain\cf1\f51\fs20\ql the patents listed by the NDA sponsor is published in the Orange Book. When an Abbreviated New Drug\plain\cf1\f51\fs20\ql Application, or ANDA, or 505(b)(2) applicant files its application with the FDA, the applicant is required to certify\plain\cf1\f51\fs20\ql to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering\plain\cf1\f51\fs20\ql methods of use for which the ANDA applicant is not seeking approval.\~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 22\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the listed patent is invalid, unenforceable or will not be infringed by the new product.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh248\row}}}\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql A certification that the new product will not infringe the already approved product\u8217?s listed patents or\plain\cf1\f51\fs20\ql that such patents are invalid or unenforceable is called a Paragraph IV certification. If the applicant does not\plain\cf1\f51\fs20\ql challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the\~\~application\plain\cf1\f51\fs20\ql will not be approved until all the listed patents claiming the referenced product have expired (other than method of\plain\cf1\f51\fs20\ql use patents involving indications for which the ANDA applicant is not seeking approval).\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If the ANDA or 505(b)(2) applicant has provided a Paragraph IV certification to the FDA, the applicant must\plain\cf1\f51\fs20\ql also send notice of the Paragraph IV certification to the NDA and patent holders once the ANDA or 505(b)(2)\plain\cf1\f51\fs20\ql application has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent\plain\cf1\f51\fs20\ql infringement lawsuit in response to the notice of the Paragraph IV certification. The filing of a patent infringement\plain\cf1\f51\fs20\ql lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from\plain\cf1\f51\fs20\ql approving the ANDA or 505(b)(2) application until the earlier of 30 months after the receipt of the Paragraph IV\plain\cf1\f51\fs20\ql notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Pediatric Studies and Exclusivity\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are\plain\cf1\f51\fs20\ql adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant\plain\cf1\f51\fs20\ql pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the\plain\cf1\f51\fs20\ql product is safe and effective. With enactment of the FDASIA in 2012, sponsors must also submit pediatric study\plain\cf1\f51\fs20\ql plans prior to the assessment data. Those plans must contain an outline of the proposed pediatric study or studies\plain\cf1\f51\fs20\ql the applicant plans to conduct, including study objectives and design, any deferral or waiver requests, and other\plain\cf1\f51\fs20\ql information required by regulation. The applicant, the FDA, and the FDA\u8217?s internal review committee must\plain\cf1\f51\fs20\ql then review the information submitted, consult with each other, and agree upon a final plan. The FDA or the\plain\cf1\f51\fs20\ql applicant may request an amendment to the plan at any time.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request\plain\cf1\f51\fs20\ql of an applicant, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of\plain\cf1\f51\fs20\ql pediatric assessments. In addition, FDA will meet early in the development process to discuss pediatric study plans\plain\cf1\f51\fs20\ql with sponsors and FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or\plain\cf1\f51\fs20\ql life-threatening diseases and by no later than ninety (90) days after FDA\u8217?s receipt of the study plan.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some\plain\cf1\f51\fs20\ql or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric\plain\cf1\f51\fs20\ql data requirements. Additional requirements and procedures relating to deferral requests and requests for extension of\plain\cf1\f51\fs20\ql deferrals are contained in the FDASIA. Unless otherwise required by regulation, the pediatric data requirements do\plain\cf1\f51\fs20\ql not apply to products with orphan designation.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted,\plain\cf1\f51\fs20\ql provides for the attachment of an additional six months of marketing protection to the term of any existing\plain\cf1\f51\fs20\ql regulatory exclusivity, including the non-patent and orphan exclusivity. This six-month exclusivity may be granted\plain\cf1\f51\fs20\ql if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data. The\plain\cf1\f51\fs20\ql data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical trial is\plain\cf1\f51\fs20\ql deemed to fairly respond to the FDA\u8217?s request, the additional protection is granted. If reports of requested\plain\cf1\f51\fs20\ql pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or\plain\cf1\f51\fs20\ql regulatory periods of exclusivity or patent protection cover the product are extended by six months. This is not a\plain\cf1\f51\fs20\ql patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another\plain\cf1\f51\fs20\ql application.\par\pard\plain\sb528\cf1\f51\fs20\qc 23\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Orphan Drug Designation and Exclusivity\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Under the Orphan Drug Act, the FDA may designate a drug product as an \u8220?orphan drug\u8221? if it is\plain\cf1\f51\fs20\ql intended to treat a rare disease or condition (generally meaning that it affects fewer than 200,000 individuals in the\plain\cf1\f51\fs20\ql United States, or more in cases in which there is no reasonable expectation that the cost of developing and making\plain\cf1\f51\fs20\ql a drug product available in the United States for treatment of the disease or condition will be recovered from sales\plain\cf1\f51\fs20\ql of the product). A company must request orphan product designation before submitting an NDA. If the request is\plain\cf1\f51\fs20\ql granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan product designation\plain\cf1\f51\fs20\ql does not convey any advantage in or shorten the duration of the regulatory review and approval process, although it\plain\cf1\f51\fs20\ql does convey certain advantages such as tax benefits and exemption from PDUFA fees.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If a product with orphan status receives the first FDA approval for the disease or condition for which it has\plain\cf1\f51\fs20\ql such designation or for a select indication or use within the rare disease or condition for which it was designated,\plain\cf1\f51\fs20\ql the product generally will receive orphan product exclusivity. Orphan product exclusivity means that the FDA may\plain\cf1\f51\fs20\ql not approve any other applications for the same product for the same indication for seven years, except in certain\plain\cf1\f51\fs20\ql limited circumstances. Competitors may receive approval of different products for the indication for which the\plain\cf1\f51\fs20\ql orphan product has exclusivity and may obtain approval for the same product but for a different indication. If a\plain\cf1\f51\fs20\ql drug or drug product designated as an orphan product ultimately receives marketing approval for an indication\plain\cf1\f51\fs20\ql broader than what was designated in its orphan product application, it may not be entitled to exclusivity.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Orphan drug exclusivity will not bar approval of another product under certain circumstances, including if a\plain\cf1\f51\fs20\ql subsequent product with the same drug for the same condition is shown to be clinically superior to the approved\plain\cf1\f51\fs20\ql product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the\plain\cf1\f51\fs20\ql company with orphan drug exclusivity is not able to meet market demand. This is the case despite an earlier court\plain\cf1\f51\fs20\ql opinion holding that the Orphan Drug Act unambiguously required the FDA to recognize orphan exclusivity\plain\cf1\f51\fs20\ql regardless of a showing of clinical superiority.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Patent Term Restoration and Extension\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql A patent claiming a new drug product may be eligible for a limited patent term extension under the Drug\plain\cf1\f51\fs20\ql Price Competition and Patent Term Restoration Act of 1984, which permits a patent restoration of up to five years\plain\cf1\f51\fs20\ql for patent term lost during product development and the FDA regulatory review. The restoration period granted is\plain\cf1\f51\fs20\ql typically one-half the time between the effective date of an IND and the submission date of an NDA, plus the time\plain\cf1\f51\fs20\ql between the submission date of an NDA and the ultimate approval date. Patent term restoration cannot be used to\plain\cf1\f51\fs20\ql extend the remaining term of a patent past a total of 14 years from the product\u8217?s approval date. Only one\plain\cf1\f51\fs20\ql patent applicable to an approved drug product is eligible for the extension, and the application for the extension\plain\cf1\f51\fs20\ql must be submitted prior to the expiration of the patent in question. A patent that covers multiple drugs for which\plain\cf1\f51\fs20\ql approval is sought can only be extended in connection with one of the approvals. The USPTO reviews and approves\plain\cf1\f51\fs20\ql the application for any patent term extension or restoration in consultation with the FDA.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql The 21\plain\cf1\f51\fs10\i\ql st\plain\cf1\f51\fs20\i\ql \~Century Cures Act\par\pard\plain\cf1\f52\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql On December 13, 2016, President Obama signed the 21st Century Cures Act, or the Cures Act, into law.\~\~The\plain\cf1\f51\fs20\ql Cures Act is designed to modernize and personalize healthcare, spur innovation and research, and streamline the\plain\cf1\f51\fs20\ql discovery and development of new therapies through increased federal funding of particular programs.\~\~It authorizes\plain\cf1\f51\fs20\ql increasing funding for FDA to spend on innovation projects.\~\~The new law also amends the Public Health Service\plain\cf1\f51\fs20\ql Act to reauthorize and expand funding for the National Institutes of Health.\~\~The Act establishes the NIH Innovation\plain\cf1\f51\fs20\ql Fund to pay for the cost of development and implementation of a strategic plan, early stage investigators and\plain\cf1\f51\fs20\ql research.\~\~It also charges NIH with leading and coordinating expanded pediatric research.\~\~Further, the Cures Act\plain\cf1\f51\fs20\ql directs the Centers for Disease Control and Prevention to expand surveillance of neurological diseases.\par\pard\plain\cf1\f52\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql With amendments to the FDCA and the Public Health Service Act, Title III of the Cures Act seeks to\plain\cf1\f51\fs20\ql accelerate the discovery, development, and delivery of new medicines and medical technologies.\~\~To that end, and\plain\cf1\f51\fs20\ql among other provisions, the Cures Act reauthorizes the priority review voucher program for certain drugs intended\plain\cf1\f51\fs20\ql to treat rare pediatric diseases; creates a new priority review voucher program for drug applications determined to\plain\cf1\f51\fs20\ql be material threat medical countermeasure applications; revises the FDCA to streamline review of combination\par\pard\plain\sb528\cf1\f51\fs20\qc 24\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql product applications; requires FDA to evaluate the potential use of \u8220?real world evidence\u8221? to help\plain\cf1\f51\fs20\ql support approval of new indications for approved drugs; provides a new \u8220?limited population\u8221? approval\plain\cf1\f51\fs20\ql pathway for antibiotic and antifungal drugs intended to treat serious or life-threatening infections; and authorizes\plain\cf1\f51\fs20\ql FDA to designate a drug as a \u8220?regenerative advanced therapy,\u8221? thereby making it eligible for certain\plain\cf1\f51\fs20\ql expedited review and approval designations.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Review and Approval of Drug Products in the European Union\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In order to market any product outside of the United States, a company must also comply with numerous and\plain\cf1\f51\fs20\ql varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and\plain\cf1\f51\fs20\ql governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of drug\plain\cf1\f51\fs20\ql products. Whether or not it obtains FDA approval for a product, the company would need to obtain the necessary\plain\cf1\f51\fs20\ql approvals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the\plain\cf1\f51\fs20\ql product in those countries or jurisdictions. The approval process ultimately varies between countries and\plain\cf1\f51\fs20\ql jurisdictions and can involve additional product testing and additional administrative review periods. The time\plain\cf1\f51\fs20\ql required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to\plain\cf1\f51\fs20\ql obtain FDA approval. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in\plain\cf1\f51\fs20\ql another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact\plain\cf1\f51\fs20\ql the regulatory process in others.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Clinical Trial Approval in the EU\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Pursuant to the European Clinical Trials Directive, a system for the approval of clinical trials in the European\plain\cf1\f51\fs20\ql Union has been implemented through national legislation of the member states. Under this system, an applicant\plain\cf1\f51\fs20\ql must obtain approval from the competent national authority of a European Union member state in which the clinical\plain\cf1\f51\fs20\ql trial is to be conducted. Furthermore, the applicant may only start a clinical trial after a competent ethics committee\plain\cf1\f51\fs20\ql has issued a favorable opinion. Clinical trial application must be accompanied by an investigational medicinal\plain\cf1\f51\fs20\ql product dossier with supporting information prescribed by the European Clinical Trials Directive and corresponding\plain\cf1\f51\fs20\ql national laws of the member states and further detailed in applicable guidance documents.\~\~In April 2014, the EU\plain\cf1\f51\fs20\ql adopted a new Clinical Trials Regulation, which will be directly applicable to and binding without the need for any\plain\cf1\f51\fs20\ql national implementing legislation.\~\~Under the new coordinated procedure for the approval of clinical trials, the\plain\cf1\f51\fs20\ql sponsor of a clinical trial will be required to submit a single application for approval of a clinical trial to a reporting\plain\cf1\f51\fs20\ql EU Member State (RMS) through an EU Portal. The submission procedure will be the same irrespective of whether\plain\cf1\f51\fs20\ql the clinical trial is to be conducted in a single EU Member State or in more than one EU Member State.\~\~The\plain\cf1\f51\fs20\ql Clinical Trials Regulation also aims to streamline and simplify the rules on safety reporting for clinical trials. The\plain\cf1\f51\fs20\ql Regulation was published on June 16, 2014 but is not expected to apply until 2019.\~ \~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Orphan Drug Designation and Exclusivity\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Regulation 141/2000 provides that a drug shall be designated as an orphan drug if its sponsor can establish:\plain\cf1\f51\fs20\ql that the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically\plain\cf1\f51\fs20\ql debilitating condition affecting not more than five in ten thousand persons in the European Community when the\plain\cf1\f51\fs20\ql application is made, or that the product is intended for the diagnosis, prevention or treatment of a life-threatening,\plain\cf1\f51\fs20\ql seriously debilitating or serious and chronic condition in the European Community and that without incentives it is\plain\cf1\f51\fs20\ql unlikely that the marketing of the drug in the European Community would generate sufficient return to justify the\plain\cf1\f51\fs20\ql necessary investment. For either of these conditions, the applicant must demonstrate that there exists no satisfactory\plain\cf1\f51\fs20\ql method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European\plain\cf1\f51\fs20\ql Community or, if such method exists, the drug will be of significant benefit to those affected by that condition.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Regulation 847/2000 sets out criteria and procedures governing designation of orphan drugs in the EU.\plain\cf1\f51\fs20\ql Specifically, an application for designation as an orphan product can be made any time prior to the filing of an\plain\cf1\f51\fs20\ql application for approval to market the product. Marketing authorization for an orphan drug leads to a ten-year\plain\cf1\f51\fs20\ql period of market exclusivity. This period may, however, be reduced to six years if, at the end of the fifth year, it is\plain\cf1\f51\fs20\ql established that the product no longer meets the criteria for orphan drug designation, for example because the\plain\cf1\f51\fs20\ql product is sufficiently profitable not to justify market exclusivity. Market exclusivity can be revoked only in very\plain\cf1\f51\fs20\ql selected cases, such as consent from the marketing authorization holder, inability to supply sufficient quantities of\plain\cf1\f51\fs20\ql the product, demonstration of \u8220?clinically relevant superiority\u8221? by a similar medicinal product, or, after\plain\cf1\f51\fs20\ql a review by\par\pard\plain\sb528\cf1\f51\fs20\qc 25\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql the Committee for Orphan Medicinal Products, requested by a member state in the fifth year of the marketing\plain\cf1\f51\fs20\ql exclusivity period (if the designation criteria are believed to no longer apply). Medicinal products designated as\plain\cf1\f51\fs20\ql orphan drugs pursuant to Regulation 141/2000 shall be eligible for incentives made available by the European\plain\cf1\f51\fs20\ql Community and by the member states to support research into, and the development and availability of, orphan\plain\cf1\f51\fs20\ql drugs.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Pharmaceutical Coverage, Pricing and Reimbursement\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA\plain\cf1\f51\fs20\ql and other government authorities. Sales of products will depend, in part, on the extent to which the costs of the\plain\cf1\f51\fs20\ql products will be covered by third-party payors, including government health programs in the United States such as\plain\cf1\f51\fs20\ql Medicare and Medicaid, commercial health insurers and managed care organizations. The process for determining\plain\cf1\f51\fs20\ql whether a payor will provide coverage for a product may be separate from the process for setting the price or\plain\cf1\f51\fs20\ql reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors are\plain\cf1\f51\fs20\ql increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness\plain\cf1\f51\fs20\ql of medical products and services and imposing controls to manage costs.\~\~Third-party payors may also limit\plain\cf1\f51\fs20\ql coverage to specific products on an approved list, or formulary, which might not include all of the approved\plain\cf1\f51\fs20\ql products for a particular indication.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In order to secure coverage and reimbursement for any product that might be approved for sale, a company\plain\cf1\f51\fs20\ql may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and\plain\cf1\f51\fs20\ql cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable regulatory\plain\cf1\f51\fs20\ql approvals. A payor\u8217?s decision to provide coverage for a drug product does not imply that an adequate\plain\cf1\f51\fs20\ql reimbursement rate will be approved. Third-party reimbursement may not be sufficient to maintain price levels high\plain\cf1\f51\fs20\ql enough to realize an appropriate return on investment in product development.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The containment of healthcare costs also has become a priority of federal, state and foreign governments and\plain\cf1\f51\fs20\ql the prices of drugs have been a focus in this effort. Governments have shown significant interest in implementing\plain\cf1\f51\fs20\ql cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution\plain\cf1\f51\fs20\ql of generic products. Adoption of price controls and cost-containment measures, and adoption of more restrictive\plain\cf1\f51\fs20\ql policies in jurisdictions with existing controls and measures, could further limit a company\u8217?s revenue\plain\cf1\f51\fs20\ql generated from the sale of any approved products. Coverage policies and third-party reimbursement rates may\plain\cf1\f51\fs20\ql change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for\plain\cf1\f51\fs20\ql which a company or its collaborators receive marketing approval, less favorable coverage policies and\plain\cf1\f51\fs20\ql reimbursement rates may be implemented in the future. In the European Union, pricing and reimbursement schemes\plain\cf1\f51\fs20\ql vary widely from country to country. Some countries provide that drug products may be marketed only after a\plain\cf1\f51\fs20\ql reimbursement price has been agreed. Some countries may require the completion of additional studies that compare\plain\cf1\f51\fs20\ql the cost-effectiveness of a particular drug candidate to currently available therapies, or so called health technology\plain\cf1\f51\fs20\ql assessments, in order to obtain reimbursement or pricing approval. For example, the European Union provides\plain\cf1\f51\fs20\ql options for its member states to restrict the range of drug products for which their national health insurance systems\plain\cf1\f51\fs20\ql provide reimbursement and to control the prices of medicinal products for human use. European Union member\plain\cf1\f51\fs20\ql states may approve a specific price for a drug product or may instead adopt a system of direct or indirect controls\plain\cf1\f51\fs20\ql on the profitability of the company placing the drug product on the market. Other member states allow companies\plain\cf1\f51\fs20\ql to fix their own prices for drug products, but monitor and control company profits. The downward pressure on\plain\cf1\f51\fs20\ql health care costs in general, particularly prescription drugs, has become intense. As a result, increasingly high\plain\cf1\f51\fs20\ql barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from\plain\cf1\f51\fs20\ql low-priced markets exert competitive pressure that may reduce pricing within a country. Any country that has price\plain\cf1\f51\fs20\ql controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing\plain\cf1\f51\fs20\ql arrangements.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 26\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\i\ql Healthcare Law and Regulation\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Healthcare providers, physicians and third-party payors play a primary role in the recommendation and\plain\cf1\f51\fs20\ql prescription of drug products that are granted marketing approval. Arrangements with providers, consultants,\plain\cf1\f51\fs20\ql third-party payors and customers are subject to broadly applicable fraud and abuse and other healthcare laws and\plain\cf1\f51\fs20\ql regulations. Such restrictions under applicable federal and state healthcare laws and regulations, include the\plain\cf1\f51\fs20\ql following:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully\plain\intbl\cf1\f51\fs20\ql soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce\plain\intbl\cf1\f51\fs20\ql or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or\plain\intbl\cf1\f51\fs20\ql service, for which payment may be made, in whole or in part, under a federal healthcare program such as\plain\intbl\cf1\f51\fs20\ql Medicare and Medicaid;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal False Claims Act imposes civil penalties, and provides for civil whistleblower or qui tam\plain\intbl\cf1\f51\fs20\ql actions, against individuals or entities for knowingly presenting, or causing to be presented, to the federal\plain\intbl\cf1\f51\fs20\ql government, claims for payment that are false or fraudulent or making a false statement to avoid, decrease\plain\intbl\cf1\f51\fs20\ql or conceal an obligation to pay money to the federal government, with potential liability including\plain\intbl\cf1\f51\fs20\ql mandatory treble damages and significant per-claim penalties, currently set at $5,500 to $11,000 per false\plain\intbl\cf1\f51\fs20\ql claim;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and\plain\intbl\cf1\f51\fs20\ql civil liability for executing a scheme to defraud any healthcare benefit program or making false statements\plain\intbl\cf1\f51\fs20\ql relating to healthcare matters;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql HIPAA, as amended by the Health Information Technology for Economic and Clinical\plain\intbl\cf1\f51\fs20\ql Health Act and their respective\~\~implementing regulations, including the Final Omnibus\plain\intbl\cf1\f51\fs20\ql Rule published in January 2013, also imposes obligations, including mandatory\plain\intbl\cf1\f51\fs20\ql contractual terms, with respect to safeguarding the privacy, security and transmission of\plain\intbl\cf1\f51\fs20\ql individually identifiable health information;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal false statements statute prohibits knowingly and willfully falsifying, concealing or covering up a\plain\intbl\cf1\f51\fs20\ql material fact or making any materially false statement in connection with the delivery of or payment for\plain\intbl\cf1\f51\fs20\ql healthcare benefits, items or services;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal transparency requirements under the Health Care Reform Law, known as the federal Physician\plain\intbl\cf1\f51\fs20\ql Payments Sunshine Act,\~\~require manufacturers of drugs, devices, biologics and medical supplies to report\plain\intbl\cf1\f51\fs20\ql to the Centers for Medicare & Medicaid Services, or CMS, within the Department of Health and Human\plain\intbl\cf1\f51\fs20\ql Services information related to payments and other transfers of value to physicians and teaching hospitals\plain\intbl\cf1\f51\fs20\ql and physician ownership and investment interests held by physicians and their immediate family members;\plain\intbl\cf1\f51\fs20\ql and\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, may\plain\intbl\cf1\f51\fs20\ql apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by\plain\intbl\cf1\f51\fs20\ql non-governmental third-party payors, including private insurers.\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh742\row}}}\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Some state laws require pharmaceutical companies to comply with the pharmaceutical industry\u8217?s\plain\cf1\f51\fs20\ql voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in\plain\cf1\f51\fs20\ql addition to requiring drug manufacturers to report information related to payments to physicians and other health\plain\cf1\f51\fs20\ql care providers or marketing expenditures. State and foreign laws also govern the privacy and security of health\plain\cf1\f51\fs20\ql information in some circumstances, many of which differ from each other in significant ways and often are not\plain\cf1\f51\fs20\ql preempted by HIPAA, thus complicating compliance efforts.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Healthcare Reform in the\plain\cf1\f51\fs20\ql United\plain\cf1\f51\fs20\i\ql States\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql A primary trend in the United States healthcare industry and elsewhere is cost containment. There have been\plain\cf1\f51\fs20\ql a number of federal and state proposals during the last several years regarding the pricing of pharmaceutical and\plain\cf1\f51\fs20\ql biopharmaceutical products, limiting coverage and reimbursement for drugs and other medical products, government\plain\cf1\f51\fs20\ql control and other changes to the healthcare system in the United States.\par\pard\plain\sb528\cf1\f51\fs20\qc 27\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql By way of example, the United States and state governments continue to propose and pass legislation\plain\cf1\f51\fs20\ql designed to reduce the cost of healthcare. In March 2010, the United States Congress enacted the Patient Protection\plain\cf1\f51\fs20\ql and Affordable Care Act, or the PPACA, which, among other things, includes changes to the coverage and payment\plain\cf1\f51\fs20\ql for products under government health care programs. Among the provisions of the PPACA of importance to\plain\sa264\cf1\f51\fs20\ql potential drug candidates are:\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?an annual, nondeductible fee on any entity that manufactures or imports specified branded\plain\li1188\cf1\f51\fs20\ql prescription drugs and biologic agents, apportioned among these entities according to their market\plain\li1188\cf1\f51\fs20\ql share in certain government healthcare programs, although this fee would not apply to sales of certain\plain\li1188\sa264\cf1\f51\fs20\ql products approved exclusively for orphan indications;\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to\plain\li1188\cf1\f51\fs20\ql offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty\plain\li1188\sa264\cf1\f51\fs20\ql level, thereby potentially increasing a manufacturer\u8217?s Medicaid rebate liability;\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?expanded manufacturers\u8217? rebate liability under the Medicaid Drug Rebate Program by\plain\li1188\cf1\f51\fs20\ql increasing the minimum rebate for both branded and generic drugs and revising the definition of\plain\li1188\cf1\f51\fs20\ql \u8220?average manufacturer price,\u8221? or AMP, for calculating and reporting Medicaid drug\plain\li1188\cf1\f51\fs20\ql rebates on outpatient prescription drug prices and extending rebate liability to prescriptions for\plain\li1188\sa264\cf1\f51\fs20\ql individuals enrolled in Medicare Advantage plans;\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug\plain\li1188\sa264\cf1\f51\fs20\ql Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;\par\pard\plain\li1188\sa264\fi-396\cf1\f51\fs20\ql \u8226?expanded the types of entities eligible for the 340B drug discount program;\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?established the Medicare Part\~D coverage gap discount program by requiring manufacturers to\plain\li1188\cf1\f51\fs20\ql provide a 50% point\u8209?of\u8209?sale\u8209?discount off the negotiated price of applicable brand\plain\li1188\cf1\f51\fs20\ql drugs to eligible beneficiaries during their coverage gap period as a condition for the\plain\li1188\sa264\cf1\f51\fs20\ql manufacturers\u8217? outpatient drugs to be covered under Medicare Part\~D;\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?established a new Patient\u8209?Centered Outcomes Research Institute to oversee, identify\plain\li1188\cf1\f51\fs20\ql priorities in, and conduct comparative clinical effectiveness research, along with funding for such\plain\li1188\sa264\cf1\f51\fs20\ql research;\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?established the Independent Payment Advisory Board, or IPAB, which has authority to recommend\plain\li1188\cf1\f51\fs20\ql certain changes to the Medicare program to reduce expenditures by the program that could result in\plain\li1188\cf1\f51\fs20\ql reduced payments for prescription drugs. However, the IPAB implementation has been not been clearly\plain\li1188\cf1\f51\fs20\ql defined. The PPACA provided that under certain circumstances, IPAB recommendations will become\plain\li1188\sa264\cf1\f51\fs20\ql law unless Congress enacts legislation that will achieve the same or greater Medicare cost savings; and\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \u8226?established the Center for Medicare and Medicaid Innovation within CMS to test innovative\plain\li1188\cf1\f51\fs20\ql payment and service delivery models to lower Medicare and Medicaid spending, potentially including\plain\li1188\cf1\f51\fs20\ql prescription drug spending. Funding has been allocated to support the mission of the Center for\plain\li1188\cf1\f51\fs20\ql Medicare and Medicaid Innovation from 2011 to 2019. Other legislative changes have been proposed\plain\li1188\cf1\f51\fs20\ql and adopted since the PPACA was enacted. These changes include the Budget Control Act of 2011,\plain\li1188\cf1\f51\fs20\ql which, among other things, led to aggregate reductions to Medicare payments to providers of up to 2%\plain\li1188\cf1\f51\fs20\ql per fiscal year that started in 2013 and will stay in effect through 2024 unless additional Congressional\plain\li1188\cf1\f51\fs20\ql action is taken, and the American Taxpayer Relief Act of 2012, which, among other things, reduced\plain\li1188\cf1\f51\fs20\ql Medicare payments to several types of providers and increased the statute of limitations period for the\plain\li1188\cf1\f51\fs20\ql government to recover overpayments to providers from three to five years. These new laws may result\plain\li1188\cf1\f51\fs20\ql in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we\plain\li1188\cf1\f51\fs20\ql may obtain for any of our product candidates for which we may obtain regulatory approval or the\plain\li1188\cf1\f51\fs20\ql frequency with which any such product candidate is prescribed or used. Further, there have been\plain\li1188\cf1\f51\fs20\ql several recent U.S. congressional inquiries and proposed state and federal legislation designed to,\plain\li1188\cf1\f51\fs20\ql among other things, bring more transparency to drug pricing, review the\par\pard\plain\sb528\cf1\f51\fs20\qc 28\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\li1188\cf1\f51\fs20\ql relationship between pricing and manufacturer patient programs, reduce the costs of drugs under\plain\li1188\cf1\f51\fs20\ql Medicare and reform government program reimbursement methodologies for drug products.\par\pard\plain\li1188\fi-396\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql These healthcare reforms, as well as other healthcare reform measures that may be adopted in the future, may\plain\cf1\f51\fs20\ql result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new\plain\cf1\f51\fs20\ql payment methodologies and additional downward pressure on the price for any approved product and/or the level of\plain\cf1\f51\fs20\ql reimbursement physicians receive for administering any approved product. Reductions in reimbursement levels may\plain\cf1\f51\fs20\ql negatively impact the prices or the frequency with which products are prescribed or administered.\~\~Any reduction in\plain\cf1\f51\fs20\ql reimbursement from Medicare or other government programs may result in a similar reduction in payments from\plain\cf1\f51\fs20\ql private payors.\~\~Since enactment of the PPACA, there have been numerous legal challenges and Congressional\plain\cf1\f51\fs20\ql actions to repeal and replace provisions of the law.\~\~In May 2017, the U.S. House of Representatives passed\plain\cf1\f51\fs20\ql legislation known as the American Health Care Act of 2017.\~\~Thereafter, the Senate Republicans introduced and\plain\cf1\f51\fs20\ql then updated a bill to replace the PPACA known as the Better Care Reconciliation Act of 2017. The Senate\plain\cf1\f51\fs20\ql Republicans also introduced legislation to repeal the PPACA without companion legislation to replace it, and a\plain\cf1\f51\fs20\ql \u8220?skinny\u8221? version of the Better Care Reconciliation Act of 2017.\~\~In addition, the Senate considered\plain\cf1\f51\fs20\ql proposed healthcare reform legislation known as the Graham-Cassidy bill.\~\~None of these measures was passed by\plain\cf1\f51\fs20\ql the U.S. Senate.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The Trump Administration has also taken executive actions to undermine or delay implementation of the\plain\cf1\f51\fs20\ql PPACA.\~\~In January 2017, President Trump signed an Executive Order directing federal agencies with authorities\plain\cf1\f51\fs20\ql and responsibilities under the PPACA to waive, defer, grant exemptions from, or delay the implementation of any\plain\cf1\f51\fs20\ql provision of the PPACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers,\plain\cf1\f51\fs20\ql health insurers, or manufacturers of pharmaceuticals or medical devices.\~\~In October 2017, the President signed a\plain\cf1\f51\fs20\ql second Executive Order allowing for the use of association health plans and short-term health insurance, which may\plain\cf1\f51\fs20\ql provide fewer health benefits than the plans sold through the PPACA exchanges.\~\~At the same time, the\plain\cf1\f51\fs20\ql Administration announced that it will discontinue the payment of cost-sharing reduction, or CSR, payments to\plain\cf1\f51\fs20\ql insurance companies until Congress approves the appropriation of funds for such CSR payments. The loss of the\plain\cf1\f51\fs20\ql CSR payments is expected to increase premiums on certain policies issued by qualified health plans under the\plain\cf1\f51\fs20\ql PPACA.\~\~A bipartisan bill to appropriate funds for CSR payments was introduced in the Senate, but the future of\plain\cf1\f51\fs20\ql that bill is uncertain.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql More recently, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by the President on\plain\cf1\f51\fs20\ql December 22, 2017, Congress repealed the \u8220?individual mandate.\u8221?\~\~The repeal of this provision, which\plain\cf1\f51\fs20\ql requires most Americans to carry a minimal level of health insurance, will become effective in 2019.\~\~According to\plain\cf1\f51\fs20\ql the Congressional Budget Office, the repeal of the individual mandate will cause 13 million fewer Americans to be\plain\cf1\f51\fs20\ql insured in 2027 and premiums in insurance markets may rise.\~\~Additionally, on January 22, 2018, President Trump\plain\cf1\f51\fs20\ql signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain\plain\cf1\f51\fs20\ql PPACA-mandated fees, including the so-called \u8220?Cadillac\u8221? tax on certain high cost\plain\cf1\f51\fs20\ql employer-sponsored insurance plans, the annual fee imposed on certain health insurance providers based on market\plain\cf1\f51\fs20\ql share, and the medical device excise tax on non-exempt medical devices.\~\~The Congress will likely consider other\plain\cf1\f51\fs20\ql legislation to replace elements of the PPACA, during the next Congressional session.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Further, there have been several recent U.S. congressional inquiries and proposed federal and proposed and\plain\cf1\f51\fs20\ql enacted state legislation designed to, among other things, bring more transparency to drug pricing, review the\plain\cf1\f51\fs20\ql relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and\plain\cf1\f51\fs20\ql reform government program reimbursement methodologies for drug products. At the federal level, Congress and the\plain\cf1\f51\fs20\ql Trump administration have each indicated that it will continue to seek new legislative and/or administrative\plain\cf1\f51\fs20\ql measures to control drug costs. At the state level, individual states are increasingly aggressive in passing legislation\plain\cf1\f51\fs20\ql and implementing regulations designed to control pharmaceutical and biological product pricing, including price or\plain\cf1\f51\fs20\ql patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and\plain\cf1\f51\fs20\ql transparency measures, and, in some cases, designed to encourage importation from other countries and bulk\plain\cf1\f51\fs20\ql purchasing. In addition, regional health care authorities and individual hospitals are increasingly using bidding\plain\cf1\f51\fs20\ql procedures to determine what pharmaceutical products and which suppliers will be included in their prescription\plain\cf1\f51\fs20\ql drug and other health care programs. These measures could reduce the ultimate demand for our products, once\plain\cf1\f51\fs20\ql approved, or put pressure on our product pricing.\par\pard\plain\cf1\f51\fs24\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 29\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf11\f51\fs24\b\ql Segment and Geographical Information\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We operate in a single operating segment. For segment and geographical financial information, see Note 2 to\plain\cf1\f51\fs20\ql the financial statements appearing elsewhere in this Annual Report on Form 10-K, which are incorporated herein by\plain\cf1\f51\fs20\ql reference.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Employees\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of February\~15, 2018, we employed 62 individuals, 41 of whom are engaged in research and development\plain\cf1\f51\fs20\ql and 21 of whom hold a Ph.D.,\~M.D., or equivalent degree. None of our employees are covered by a collective\plain\cf1\f51\fs20\ql bargaining agreement, and we consider relations with our employees to be good.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Corporate Information\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We were incorporated in Delaware in 1989 and our offices are located at 167 Sidney Street, Cambridge,\plain\cf1\f51\fs20\ql Massachusetts 02139 and 505 Eagleview Boulevard, Suite 212, Exton, Pennsylvania 19341.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Information Available on the Internet\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our internet address is www.iderapharma.com. The contents of our website are not part of this Annual Report\plain\cf1\f51\fs20\ql on Form\~10-K and our internet address is included in this document as an inactive textual reference. We make\plain\cf1\f51\fs20\ql available free of charge through our web site our Annual Reports on Form\~10-K, Quarterly Reports on Form\~10-Q,\plain\cf1\f51\fs20\ql Current Reports on Form\~8-K and amendments to these reports filed or furnished pursuant to Section\~13(a) or 15(d)\plain\cf1\f51\fs20\ql of the Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after\plain\cf1\f51\fs20\ql we electronically file or furnish such materials to the Securities and Exchange Commission, or the SEC.\par\pard\plain\sb528\cf1\f51\fs20\qc 30\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_2}{\*\bkmkend item_1_3_2}\par\pard\plain\cf11\f51\fs24\b\qj Item 1A. RISK FACTORS.{\*\bkmkstart item1ariskfactors_908641_1211227}{\*\bkmkend item1ariskfactors_908641_1211227}\par\pard\plain\cf11\f51\fs24\qc \~\par\pard\plain\cf11\f51\fs24\b\qc RISK FACTORS\par\pard\plain\cf12\f51\fs24\qc \~\par\pard\plain\cf1\f51\fs20\i\qj Investing in our securities involves a high degree of risk. You should carefully consider the risks and uncertainties\plain\cf1\f51\fs20\i\qj described below in addition to the other information included or incorporated by reference in this{\*\bkmkstart _cp_text_1_273_12112272}{\*\bkmkend _cp_text_1_273_12112272}\plain\cf1\f51\fs20\i\qj Annual Report on\plain\cf1\f51\fs20\i\qj Form 10-K before purchasing{\*\bkmkstart _cp_text_4_274_12112272}{\*\bkmkend _cp_text_4_274_12112272}\plain\cf1\f51\fs20\i\qj our common stock. Our business, financial condition and results of operations could\plain\cf1\f51\fs20\i\qj be materially and adversely affected by any of these and currently unknown risks or uncertainties. In that case, the\plain\sa132\cf1\f51\fs20\i\qj market price of our common stock could decline, and you may lose all or part of your investment in our securities.\par\pard\plain\cf1\f51\fs20\qj \~{\*\bkmkstart _cp_text_1_276_12112272}{\*\bkmkend _cp_text_1_276_12112272}\par\pard\plain\cf1\f51\fs20\b\qc Risks Relating to the Mergers\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\i\ql Completion of the proposed BioCryst merger is{\*\bkmkstart _cp_text_4_325_12112272}{\*\bkmkend _cp_text_4_325_12112272}\plain\cf1\f51\fs20\b\i\ql subject to conditions and if these conditions are not satisfied or\plain\cf1\f51\fs20\b\i\ql waived, the merger will not be completed.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql On January 21, 2018, we announced that we had entered into the Merger Agreement with{\*\bkmkstart _cp_text_4_328_12112272}{\*\bkmkend _cp_text_4_328_12112272}\plain\cf1\f51\fs20\ql BioCryst, Holdco,\plain\cf1\f51\fs20\ql Merger Sub A{\*\bkmkstart _cp_text_1_329_12112272}{\*\bkmkend _cp_text_1_329_12112272}\plain\cf1\f51\fs20\ql and{\*\bkmkstart _cp_text_4_330_12112272}{\*\bkmkend _cp_text_4_330_12112272}\plain\cf1\f51\fs20\ql Merger Sub B, pursuant to which (i)\~Merger Sub A will be merged with and into us, with us\plain\cf1\f51\fs20\ql surviving as a{\*\bkmkstart _cp_text_4_332_12112272}{\*\bkmkend _cp_text_4_332_12112272}\plain\cf1\f51\fs20\ql wholly owned subsidiary of Holdco, and (ii){\*\bkmkstart _cp_text_4_334_12112272}{\*\bkmkend _cp_text_4_334_12112272}\plain\cf1\f51\fs20\ql Merger Sub B{\*\bkmkstart _cp_text_4_335_12112272}{\*\bkmkend _cp_text_4_335_12112272}\plain\cf1\f51\fs20\ql will be{\*\bkmkstart _cp_text_1_336_12112272}{\*\bkmkend _cp_text_1_336_12112272}\plain\cf1\f51\fs20\ql merged with and into BioCryst,\plain\cf1\f51\fs20\ql with BioCryst surviving as a wholly owned subsidiary{\*\bkmkstart _cp_text_4_337_12112272}{\*\bkmkend _cp_text_4_337_12112272}\plain\cf1\f51\fs20\ql of Holdco. \~{\*\bkmkstart _cp_text_4_339_12112272}{\*\bkmkend _cp_text_4_339_12112272}\plain\cf1\f51\fs20\ql The consummation of the Mergers is subject to\plain\cf1\f51\fs20\ql customary closing conditions, including (i)\~the adoption of the Merger Agreement by the affirmative vote of the\plain\cf1\f51\fs20\ql holders of a majority of all outstanding shares of our{\*\bkmkstart _cp_text_4_341_12112272}{\*\bkmkend _cp_text_4_341_12112272}\plain\cf1\f51\fs20\ql capital stock entitled to vote thereon, (ii)\~the adoption of the\plain\cf1\f51\fs20\ql Merger Agreement by the affirmative vote of the holders of a majority of all outstanding shares of BioCryst\plain\cf1\f51\fs20\ql common stock{\*\bkmkstart _cp_text_4_343_12112272}{\*\bkmkend _cp_text_4_343_12112272}\plain\cf1\f51\fs20\ql entitled to vote thereon,{\*\bkmkstart _cp_text_4_344_12112272}{\*\bkmkend _cp_text_4_344_12112272}\plain\cf1\f51\fs20\ql (iii)\~the absence of any adverse law or order promulgated, entered, enforced,\plain\cf1\f51\fs20\ql enacted or issued by any governmental entity that prohibits, restrains or makes illegal the consummation of the\plain\cf1\f51\fs20\ql Mergers, (iv)\~the shares of Holdco{\*\bkmkstart _cp_text_1_345_12112272}{\*\bkmkend _cp_text_1_345_12112272}\plain\cf1\f51\fs20\ql common stock{\*\bkmkstart _cp_text_4_346_12112272}{\*\bkmkend _cp_text_4_346_12112272}\plain\cf1\f51\fs20\ql to be issued in the Mergers being approved for listing on the\plain\cf1\f51\fs20\ql Nasdaq Global Select Market, (v)\~the expiration or termination of the waiting period under the Hart-Scott-Rodino\plain\cf1\f51\fs20\ql Antitrust Improvements Act of 1976 and other material government approvals, (vi)\~the SEC{\*\bkmkstart _cp_text_4_348_12112272}{\*\bkmkend _cp_text_4_348_12112272}\plain\cf1\f51\fs20\ql having declared\plain\cf1\f51\fs20\ql effective the Form\~S-4 Registration Statement of Holdco which will contain the joint proxy statement/prospectus of\plain\cf1\f51\fs20\ql the parties in connection with the Mergers, (vii)\~subject to certain materiality exceptions, the accuracy of certain\plain\cf1\f51\fs20\ql representations and warranties of us and BioCryst, respectively, contained in the Merger Agreement and the\plain\cf1\f51\fs20\ql compliance by each party with the covenants contained in the Merger Agreement, (viii)\~the receipt of certain\plain\cf1\f51\fs20\ql opinions from legal counsel regarding the intended tax treatment of the Mergers and (ix)\~the absence of a material\plain\cf1\f51\fs20\ql adverse effect with respect to us and BioCryst, respectively.{\*\bkmkstart _cp_text_1_350_12112272}{\*\bkmkend _cp_text_1_350_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The failure to satisfy all of the required conditions could delay the completion of the Mergers by a significant\plain\cf1\f51\fs20\ql period of time or prevent it from occurring. Any delay in completing the Mergers could cause us to not realize\plain\cf1\f51\fs20\ql some or all of the benefits that we expect to achieve if the Mergers are successfully completed within the expected\plain\cf1\f51\fs20\ql timeframe.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If we are unable to complete the proposed Mergers, we may have incurred substantial expense and diverted\plain\cf1\f51\fs20\ql significant management time and resources from our ongoing business{\*\bkmkstart _cp_text_4_352_12112272}{\*\bkmkend _cp_text_4_352_12112272}\plain\cf1\f51\fs20\ql . In addition, if the Merger Agreement is\plain\cf1\f51\fs20\ql terminated{\*\bkmkstart _cp_text_1_353_12112272}{\*\bkmkend _cp_text_1_353_12112272}\plain\cf1\f51\fs20\ql under certain circumstances specified{\*\bkmkstart _cp_text_4_354_12112272}{\*\bkmkend _cp_text_4_354_12112272}\plain\cf1\f51\fs20\ql in the{\*\bkmkstart _cp_text_4_355_12112272}{\*\bkmkend _cp_text_4_355_12112272}\plain\cf1\f51\fs20\ql Merger Agreement, we{\*\bkmkstart _cp_text_4_357_12112272}{\*\bkmkend _cp_text_4_357_12112272}\plain\cf1\f51\fs20\ql may be required to pay{\*\bkmkstart _cp_text_1_358_12112272}{\*\bkmkend _cp_text_1_358_12112272}\plain\cf1\f51\fs20\ql BioCryst{\*\bkmkstart _cp_text_4_359_12112272}{\*\bkmkend _cp_text_4_359_12112272}\plain\cf1\f51\fs20\ql a\plain\cf1\f51\fs20\ql termination fee of $25\~million{\*\bkmkstart _cp_text_1_360_12112272}{\*\bkmkend _cp_text_1_360_12112272}\plain\cf1\f51\fs20\ql or{\*\bkmkstart _cp_text_4_361_12112272}{\*\bkmkend _cp_text_4_361_12112272}\plain\cf1\f51\fs20\ql a fixed expense reimbursement amount of $6 million.{\*\bkmkstart _cp_text_1_363_12112272}{\*\bkmkend _cp_text_1_363_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql There can be no assurance that the conditions to{\*\bkmkstart _cp_text_4_364_12112272}{\*\bkmkend _cp_text_4_364_12112272}\plain\cf1\f51\fs20\ql closing of the Mergers{\*\bkmkstart _cp_text_1_365_12112272}{\*\bkmkend _cp_text_1_365_12112272}\plain\cf1\f51\fs20\ql will be satisfied or waived or that{\*\bkmkstart _cp_text_4_366_12112272}{\*\bkmkend _cp_text_4_366_12112272}\plain\cf1\f51\fs20\ql the\plain\cf1\f51\fs20\ql Mergers will be completed.{\*\bkmkstart _cp_text_1_368_12112272}{\*\bkmkend _cp_text_1_368_12112272}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Combining Idera{\*\bkmkstart _cp_text_4_369_12112272}{\*\bkmkend _cp_text_4_369_12112272}\plain\cf1\f51\fs20\b\i\ql and BioCryst{\*\bkmkstart _cp_text_1_370_12112272}{\*\bkmkend _cp_text_1_370_12112272}\plain\cf1\f51\fs20\b\i\ql may be more difficult, costly or time consuming than expected and the anticipated\plain\cf1\f51\fs20\b\i\ql benefits and cost savings of the proposed Mergers may not be realized.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are operating and, until the completion of the Mergers, will continue to operate independently of\plain\cf1\f51\fs20\ql BioCryst. The success of the Mergers, including anticipated benefits and cost savings, will depend, in part, on our\plain\cf1\f51\fs20\ql ability to successfully combine and integrate the businesses. It is possible that the pendency of the Mergers and/or\plain\cf1\f51\fs20\ql the integration process could result in the loss of key employees, higher than expected costs, diversion of\plain\cf1\f51\fs20\ql management attention, the disruption of our ongoing businesses or inconsistencies in standards, controls,\par\pard\plain\sb528\cf1\f51\fs20\qc 31\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql procedures and policies that adversely affect the combined company\u8217?s ability to maintain relationships with\plain\cf1\f51\fs20\ql customers, vendors and employees or to achieve the anticipated benefits and cost savings of the Mergers.{\*\bkmkstart _cp_text_1_372_12112272}{\*\bkmkend _cp_text_1_372_12112272}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We will incur transaction fees, including legal, regulatory and other costs associated with closing the\plain\cf1\f51\fs20\ql transaction, as well as expenses relating to formulating and implementing integration plans, including facilities and\plain\cf1\f51\fs20\ql systems consolidation costs and employment-related costs. We continue to assess the magnitude of these costs, and\plain\cf1\f51\fs20\ql additional unanticipated costs may be incurred{\*\bkmkstart _cp_text_4_373_12112272}{\*\bkmkend _cp_text_4_373_12112272}\plain\cf1\f51\fs20\ql in the{\*\bkmkstart _cp_text_1_374_12112272}{\*\bkmkend _cp_text_1_374_12112272}\plain\cf1\f51\fs20\ql Mergers and the integration of the two companies\u8217?\plain\cf1\f51\fs20\ql businesses. While we expect that the elimination of duplicative costs as well as the realization of other efficiencies\plain\cf1\f51\fs20\ql related to the integration of the businesses should allow us to offset integration-related costs over time, this net\plain\cf1\f51\fs20\ql benefit may not be achieved in the near term or at all. As part of the integration process, we may also attempt to\plain\cf1\f51\fs20\ql divest certain assets of the{\*\bkmkstart _cp_text_4_375_12112272}{\*\bkmkend _cp_text_4_375_12112272}\plain\cf1\f51\fs20\ql combined company,{\*\bkmkstart _cp_text_4_376_12112272}{\*\bkmkend _cp_text_4_376_12112272}\plain\cf1\f51\fs20\ql which may not be{\*\bkmkstart _cp_text_1_377_12112272}{\*\bkmkend _cp_text_1_377_12112272}\plain\cf1\f51\fs20\ql possible on favorable terms, or at all, or if\plain\cf1\f51\fs20\ql successful, may change the profile of the combined company. If we experience difficulties with the integration\plain\cf1\f51\fs20\ql process, the anticipated benefits of the Mergers may not be realized fully or at all, or may take longer to realize\plain\sa132\cf1\f51\fs20\ql than anticipated.\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\qc Risks Relating to Our Financial Results and Need for Financing\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\i\qj We will need additional financing, which may be difficult to obtain. Our failure to obtain necessary financing or\plain\cf1\f51\fs20\b\i\qj doing so on unattractive terms could result in the termination of our operations and the sale and license of our\plain\cf1\f51\fs20\b\i\qj assets or otherwise adversely affect our research and development programs and other operations.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql We had cash, cash equivalents and investments of approximately ${\*\bkmkstart _cp_text_1_278_12112272}{\*\bkmkend _cp_text_1_278_12112272}\plain\cf1\f51\fs20\ql 112.6 million at December\~31, 201{\*\bkmkstart _cp_text_1_281_12112272}{\*\bkmkend _cp_text_1_281_12112272}\plain\cf1\f51\fs20\ql 7. We\plain\cf1\f51\fs20\ql believe that, based on our current operating plan, our existing cash, cash equivalents and investments{\*\bkmkstart _cp_text_1_285_12112272}{\*\bkmkend _cp_text_1_285_12112272}\plain\cf1\f51\fs20\ql , \~will enable\plain\cf1\f51\fs20\ql us to fund our operations into the second quarter of 2019. Specifically, we believe that our available funds will be\plain\sa132\cf1\f51\fs20\ql sufficient to enable us to:
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql complete the dose-finding portion of our ongoing Phase 1/2 clinical trial of IMO-2125 in\plain\intbl\cf1\f51\fs20\ql combination with pembrolizumab in anti-PD1 refractory metastatic melanoma and complete\plain\intbl\sa132\cf1\f51\fs20\ql enrollment in the Phase 2 portion of this trial in combination with iplilimumab;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql initiate a Phase 3 clinical trial of IMO-2125 in combination with iplilimumab for the treatment of\plain\intbl\sa132\cf1\f51\fs20\ql anti-PD1 refractory metastatic melanoma;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql continue to enroll patients in our Phase 1b intra-tumoral monotherapy clinical trial of\plain\intbl\sa132\cf1\f51\fs20\ql IMO-2125 in multiple refractory tumor types; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql complete our ongoing Phase 2 clinical trial of IMO-8400 in patients with dermatomyositis.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\li990\cf1\f51\fs24\ql \~\par\pard\plain\fi594\cf1\f51\fs20\qj We expect that we will need to raise additional funds in order to complete these trials, conduct any other\plain\cf1\f51\fs20\qj clinical development of our TLR drug candidates or to conduct any other development of our nucleic acid chemistry\plain\cf1\f51\fs20\qj technology, and to fund our operations. We are seeking and expect to continue to seek additional funding through\plain\cf1\f51\fs20\qj collaborations, the sale or license of assets or financings of equity or debt securities. We believe that the key factors\plain\cf1\f51\fs20\qj that will affect our ability to obtain funding are:
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj the results of our clinical and preclinical development activities in our rare disease program, our\plain\intbl\cf1\f51\fs20\qj immuno-oncology program and our nucleic acid chemistry research program, and our ability to advance\plain\intbl\sa132\cf1\f51\fs20\qj our drug candidates and nucleic acid chemistry technology on the timelines anticipated;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f51\fs20\qj the cost, timing, and outcome of regulatory reviews;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1012
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj competitive and potentially competitive products and technologies and investors' receptivity to\plain\intbl\cf1\f51\fs20\qj our drug candidates and the technology underlying them in light of competitive products and\plain\intbl\sa110\cf1\f51\fs20\qj technologies;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1012\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh765
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj the receptivity of the capital markets to financings by biotechnology companies generally and companies\plain\intbl\sa110\cf1\f51\fs20\qj with drug candidates and technologies such as ours specifically; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh765\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa264\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj our ability to enter into additional collaborations with biotechnology and pharmaceutical companies and\plain\intbl\sa264\cf1\f51\fs20\qj the success of such collaborations.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}\pard\plain\fi528\cf1\f51\fs20\ql In addition, increases in expenses or delays in clinical development may adversely impact our cash position\plain\cf1\f51\fs20\ql and require additional funds or cost reductions.\par\pard\plain\sb528\cf1\f51\fs20\qc 32\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_295_12112272}{\*\bkmkend _cp_text_1_295_12112272}\par\pard\plain\fi528\cf1\f51\fs20\ql Financing may not be available to us when we need it or may not be available to us on favorable or\plain\cf1\f51\fs20\ql acceptable terms or at all. We could be required to seek funds through collaborative alliances or through other\plain\cf1\f51\fs20\ql means that may require us to relinquish rights to some of our technologies, drug candidates or drugs that we would\plain\cf1\f51\fs20\ql otherwise pursue on our own. In addition, if we raise additional funds by issuing equity securities, our then existing\plain\cf1\f51\fs20\ql stockholders will experience dilution. The terms of any financing may adversely affect the holdings or the rights of\plain\cf1\f51\fs20\ql existing stockholders. An equity financing that involves existing stockholders may cause a concentration of\plain\cf1\f51\fs20\ql ownership. Debt financing, if available, may involve agreements that include covenants limiting or restricting our\plain\cf1\f51\fs20\ql ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends,\plain\cf1\f51\fs20\ql and are likely to include rights that are senior to the holders of our common stock. Any additional debt or equity\plain\cf1\f51\fs20\ql financing may contain terms which are not favorable to us or to our stockholders, such as liquidation and other\plain\cf1\f51\fs20\ql preferences, or liens or other restrictions on our assets. As discussed in Note 12 to the financial statements\plain\cf1\f51\fs20\ql appearing elsewhere in this Annual Report on Form 10-K, additional equity financings may also result in\plain\cf1\f51\fs20\ql cumulative changes in ownership over a three-year period in excess of 50% which would limit the amount of net\plain\cf1\f51\fs20\ql operating loss and tax credit carryforwards that we may utilize in any one year.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql If we are unable to obtain adequate funding on a timely basis or at all, we will be required to terminate,\plain\cf1\f51\fs20\ql modify or delay preclinical or clinical trials of one or more of our drug candidates, significantly curtail or terminate\plain\cf1\f51\fs20\ql discovery or development programs for new drug candidates or relinquish rights to portions of our technology, drug\plain\cf1\f51\fs20\ql candidates and/or products.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We have incurred substantial losses and expect to continue to incur losses. We will not be successful unless we\plain\cf1\f51\fs20\b\i\qj reverse this trend.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\ql We have incurred losses in every year since our inception, except for 2002, 2008, and 2009 when our\plain\cf1\f51\fs20\ql recognition of revenues under license and collaboration agreements resulted in our reporting net income for those\plain\cf1\f51\fs20\ql years. As of December\~31, 2017, we had an accumulated deficit of ${\*\bkmkstart _cp_text_1_299_12112272}{\*\bkmkend _cp_text_1_299_12112272}\plain\cf1\f51\fs20\ql 604.5 million. Since January 1, 2001, we have\plain\cf1\f51\fs20\ql primarily been involved in the development of our TLR pipeline. From January 1, 2001 to December\~31, 2017, we\plain\cf1\f51\fs20\ql incurred losses of ${\*\bkmkstart _cp_text_1_303_12112272}{\*\bkmkend _cp_text_1_303_12112272}\plain\cf1\f51\fs20\ql 344.3 million. We incurred losses of $260.2 million prior to December 31, 2000, during which\plain\cf1\f51\fs20\ql time we were primarily involved in the development of earlier generation antisense technology. These losses, among\plain\cf1\f51\fs20\ql other things, have had and will continue to have an adverse effect on our stockholders' equity, total assets, and\plain\cf1\f51\fs20\ql working capital.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We have never had any products of our own available for commercial sale and have received no revenues\plain\cf1\f51\fs20\ql from the sale of drugs. As of December\~31, 2017, substantially all of our revenues have been from collaborative and\plain\cf1\f51\fs20\ql license agreements. We have devoted substantially all of our efforts to research and development, including clinical\plain\cf1\f51\fs20\ql trials, and have not completed development of any drug candidates. Because of the numerous risks and uncertainties\plain\cf1\f51\fs20\ql associated with developing drugs, we are unable to predict the extent of any future losses, whether or when any of\plain\cf1\f51\fs20\ql our drug candidates will become commercially available, or when we will become profitable, if at all. We expect to\plain\cf1\f51\fs20\ql incur substantial operating losses in future periods.{\*\bkmkstart _cp_text_1_307_12112272}{\*\bkmkend _cp_text_1_307_12112272}\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\qc Risks Relating to Our Business, Strategy and Industry\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\fi528\cf1\f51\fs20\b\i\ql We are depending heavily on the development of TLR-targeted drug candidates in our immuno-oncology\plain\cf1\f51\fs20\b\i\ql program and for the treatment of certain rare diseases and on the development of drug candidates using our\plain\cf1\f51\fs20\b\i\ql nucleic acid chemistry technology. If we terminate the development of any of our programs or any of our drug\plain\cf1\f51\fs20\b\i\ql candidates in such programs, are unable to successfully develop and commercialize any of our drug candidates,\plain\cf1\f51\fs20\b\i\ql or experience significant delays in doing so, our business may be materially harmed.\par\pard\plain\fi528\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\ql We have invested a significant portion of our time and financial resources in the development of\plain\cf1\f51\fs20\ql TLR-targeted clinical-stage drug candidates as part of our immuno-oncology and rare disease programs. In the\plain\cf1\f51\fs20\ql future, we intend to invest a significant portion of our time and financial resources in the development of our\plain\cf1\f51\fs20\ql TLR-targeted candidates in our immuno-oncology program and for the treatment of certain rare diseases. We also\plain\cf1\f51\fs20\ql may invest substantial time and resources to further advance the development of drug candidates under our nucleic\plain\sa132\cf1\f51\fs20\ql acid chemistry research program. For instance:
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we are conducting a Phase 1/2 clinical trial of IMO-2125, administered intra-tumorally, in combination\plain\intbl\cf1\f51\fs20\ql with ipilimumab or pembrolizumab in patients with anti-PD1 refractory metastatic melanoma{\*\bkmkstart _cp_text_1_405_12112272}{\*\bkmkend _cp_text_1_405_12112272}\plain\intbl\sa132\cf1\f51\fs20\ql , a Phase 3\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}\pard\plain\sb528\cf1\f51\fs20\qc 33\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}
\par\pard\plain
{\trowd\cellx9688\trrh900
\pard\plain\intbl\li990\cf1\f51\fs20\ql clinical trial of IMO-2125, administered intra-tumorally, in combination with ipilimumab in patients\plain\intbl\li990\cf1\f51\fs20\ql with anti-PD1 refractory metastatic melanoma, and a Phase 1b trial of IMO-2125, administered\plain\intbl\li990\sa132\cf1\f51\fs20\ql intra-tumorally, as a monotherapy in patients with refractory solid tumors; \~\cell{
{\trowd\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we may conduct additional clinical trials of IMO-2125 in our immuno-oncology program in combination\plain\intbl\sa132\cf1\f51\fs20\ql with checkpoint inhibitors for the treatment of multiple tumor types;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we are conducting a Phase 2 clinical trial of IMO-8400 in patients with dermatomyositis;\plain\intbl\sa132\cf1\f51\fs20\ql and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh878
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb110\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb110\cf1\f51\fs20\ql we are developing compounds in our nucleic acid chemistry research program and plan to make a\plain\intbl\cf1\f51\fs20\ql development decision for IDRA-008 based upon the totality of IND-enabling studies and our comparator\plain\intbl\cf1\f51\fs20\ql pharmacology study with Volanesorsen.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh878\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We anticipate that our ability to generate product revenues will depend heavily on the successful development\plain\cf1\f51\fs20\ql and commercialization of our TLR drug candidates in our rare disease and immuno-oncology programs, and the\plain\cf1\f51\fs20\ql successful identification, development and commercialization of drug candidates in our nucleic acid chemistry\plain\cf1\f51\fs20\ql research program.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our ability to generate milestone and royalty revenues under any of our current collaborations, including our\plain\cf1\f51\fs20\ql collaborations with Vivelix and GSK, and under any other collaboration that we enter into with respect to our other\plain\cf1\f51\fs20\ql programs, will depend on the development and commercialization of the drug candidates being developed under the\plain\cf1\f51\fs20\ql collaborations.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our efforts and the efforts of our collaborators, including Vivelix and GSK, to develop and commercialize\plain\cf1\f51\fs20\ql compounds, are at an early stage and are subject to many challenges. For instance, we previously experienced a\plain\cf1\f51\fs20\ql setback with respect to our program for IMO-2125 for hepatitis C. In April 2011, we chose to delay initiation of\plain\cf1\f51\fs20\ql our planned 12-week Phase 2 randomized clinical trial of IMO-2125 plus ribavirin in treatment-na\u239?ve,\plain\cf1\f51\fs20\ql genotype 1 hepatitis C virus, or HCV, patients based on observations of lymphoproliferative malignancies in an\plain\cf1\f51\fs20\ql ongoing 26-week chronic nonclinical toxicology study of IMO-2125 in rodents. We subsequently completed a\plain\cf1\f51\fs20\ql 39-week chronic nonclinical toxicology study of IMO-2125 in non-human primates in which there were no similar\plain\cf1\f51\fs20\ql observations. Also, in September 2016, we suspended our development program of IMO-8400 for the treatment of\plain\cf1\f51\fs20\ql B-cell lymphomas and suspended our ongoing Phase 1/2 clinical trials of IMO-8400 in patients with\plain\cf1\f51\fs20\ql Waldenstr\u246?m's macroglobulinemia and in patients with diffuse large B-cell lymphoma, or DLBCL, harboring\plain\cf1\f51\fs20\ql the MYD88 L265P oncogenic mutation due to several factors, including the lack of a strong clinical signal for\plain\cf1\f51\fs20\ql Waldenstr\u246?m's macroglobulinemia patients and the inability to adequately enroll patients with DLBCL.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We have entered into and expect to continue to seek to enter into collaborative alliances with pharmaceutical\plain\cf1\f51\fs20\ql companies to advance our TLR agonists and antagonist candidates and with respect to additional applications of our\plain\cf1\f51\fs20\ql nucleic acid chemistry technology program. Our previous setbacks with respect to our program for IMO-2125 in\plain\cf1\f51\fs20\ql patients with chronic hepatitis C virus and our program for IMO-8400 in patients with B-cell lymphomas could\plain\cf1\f51\fs20\ql negatively impact our ability to license any of such compounds, or any of our other compounds, to a third party.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our ability to successfully develop and commercialize these drug candidates, or other potential drug\plain\cf1\f51\fs20\ql candidates, will depend on our ability to overcome these recent challenges and on several factors, including the\plain\sa132\cf1\f51\fs20\ql following:
\par\pard\plain
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\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the drug candidates demonstrating an acceptable safety profile in nonclinical toxicology studies and\plain\intbl\sa132\cf1\f51\fs20\qj during clinical trials;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj timely enrollment in clinical trials of IMO-8400, IMO-2125 and other drug candidates, which\plain\intbl\sa132\cf1\f51\fs20\qj may be slower than anticipated, potentially resulting in significant delays;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj satisfying conditions imposed on us and/or our collaborators by the FDA or equivalent foreign\plain\intbl\sa132\cf1\f51\fs20\qj regulatory authorities regarding the scope or design of clinical trials;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the ability to demonstrate to the satisfaction of the FDA, or equivalent foreign regulatory authorities, the\plain\intbl\sa132\cf1\f51\fs20\qj safety and efficacy of the drug candidates through current and future clinical trials;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh630
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj timely receipt of necessary marketing approvals from the FDA and equivalent foreign regulatory\plain\intbl\sa132\cf1\f51\fs20\qj authorities;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh630\row}}}\pard\plain\sb528\cf1\f51\fs20\qc 34\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the ability to combine our drug candidates and the drug candidates being developed by our\plain\intbl\sa132\cf1\f51\fs20\qj collaborators and any other collaborators safely and successfully with other therapeutic agents;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj achieving and maintaining compliance with all regulatory requirements applicable to the\plain\intbl\sa132\cf1\f51\fs20\qj products;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\qj establishment of commercial manufacturing arrangements with third-party manufacturers;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the ability to secure orphan drug exclusivity for our drug candidates either alone or in combination with\plain\intbl\sa132\cf1\f51\fs20\qj other products;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the successful commercial launch of the drug candidates, assuming FDA approval is obtained, whether\plain\intbl\sa132\cf1\f51\fs20\qj alone or in combination with other products;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj acceptance of the products as safe and effective by patients, the medical community, and third-party\plain\intbl\sa132\cf1\f51\fs20\qj payors;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\qj changes in treatment regimens;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\qj favorable market conditions in which to raise additional capital;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\qj the strength of our intellectual property portfolio in the United States and abroad; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh630
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb110\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb110\cf1\f51\fs20\qj a continued acceptable safety and efficacy profile of the drug candidates following marketing\plain\intbl\cf1\f51\fs20\qj approval.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh630\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj We are in the early stages of developing our TLR9 agonists in combination with checkpoint inhibitors, which is a\plain\cf1\f51\fs20\b\i\qj novel technology, and our efforts may not be successful or result in any approved and marketable products.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\ql In June 2015, we entered into a strategic clinical research alliance with MD Anderson to advance clinical\plain\cf1\f51\fs20\ql development of TLR9 agonists in combination with checkpoint inhibitors. We initiated the first trial from the\plain\cf1\f51\fs20\ql research alliance, a Phase 1/2 clinical trial to assess the safety and efficacy of IMO-2125, administered\plain\cf1\f51\fs20\ql intra-tumorally in combination with ipilimumab, a CTLA4 antibody, in patients with metastatic melanoma\plain\cf1\f51\fs20\ql (anti-PD1 refractory) in the fourth quarter of 2015. While we have evaluated the safety profile of IMO-2125 in\plain\cf1\f51\fs20\ql previous trials, in those trials we evaluated the safety profile of IMO-2125 by subcutaneous injection and not by\plain\cf1\f51\fs20\ql intra-tumoral injection. In addition, while, as a marketed product, the safety profile of ipilimumab is known, the\plain\cf1\f51\fs20\ql safety profile of the combination of IMO-2125 and ipilimumab has not been evaluated in previous trials. These\plain\cf1\f51\fs20\ql factors may result in participating subjects experiencing serious adverse events or undesirable side effects or\plain\cf1\f51\fs20\ql exposure to unacceptable health risks requiring us to suspend or terminate any clinical trials that we may conduct of\plain\cf1\f51\fs20\ql IMO-2125 in combination with ipilimumab, or any other checkpoint inhibitor. Furthermore, we have expanded the\plain\cf1\f51\fs20\ql Phase 1/2 clinical trial to include the assessment of safety and efficacy of IMO-2125, administered intra-tumorally\plain\cf1\f51\fs20\ql in combination with pembrolizumab, an anti-PD1 antibody in patients with metastatic melanoma (anti-PD1\plain\cf1\f51\fs20\ql refractory). While, as a marketed product, the safety profile of pembrolizumab is known, the safety profile of the\plain\cf1\f51\fs20\ql combination of IMO-2125 and pembrolizumab has not been evaluated in previous trials and may result in\plain\cf1\f51\fs20\ql participating subjects experiencing serious adverse events or undesirable side effects or exposure to unacceptable\plain\cf1\f51\fs20\ql health risks requiring us to suspend or terminate any clinical trials that we may conduct of IMO-2125 in\plain\cf1\f51\fs20\ql combination with pembrolizumab, or any other checkpoint inhibitor.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We are in the early stages of developing our nucleic acid chemistry program, which is a novel technology, and\plain\cf1\f51\fs20\b\i\qj our efforts may not be successful or result in any approved and marketable products.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We are in the early stages of developing our nucleic acid chemistry technology program, and the scientific\plain\cf1\f51\fs20\ql evidence to support the feasibility of developing drugs based on this technology is limited.\~\~In addition, the FDA has\plain\cf1\f51\fs20\ql relatively limited experience with nucleic acid therapeutics, which may increase the complexity, uncertainty and\plain\cf1\f51\fs20\ql length of the regulatory review process for our drug candidates. To date, the FDA has approved only five nucleic\plain\cf1\f51\fs20\ql acid-based therapeutics for marketing and commercialization, and the FDA and its foreign counterparts have not yet\plain\cf1\f51\fs20\ql established any definitive policies, practices or guidelines specifically in relation to these drugs.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql The future success of our nucleic acid chemistry technology program depends on our success in identifying\plain\cf1\f51\fs20\ql and developing marketable products based on such technology and the effectiveness of our platform. Although the\plain\cf1\f51\fs20\ql results of our preclinical studies to date have been supportive of the viability of this technology, it is unknown\plain\cf1\f51\fs20\ql whether these results are indicative of results that may be obtained in any future clinical trials that we may\par\pard\plain\sb528\cf1\f51\fs20\qc 35\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql conduct. We are currently undertaking an analysis of priority oncology and rare disease indications for development\plain\cf1\f51\fs20\ql of drug candidates generated from our nucleic acid chemistry technology. We are also conducting preliminary\plain\cf1\f51\fs20\ql analysis of nucleic acid chemistry compounds for an undisclosed renal gene target.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql However, many steps must be successfully achieved prior to the declaration of a nucleic acid chemistry drug\plain\cf1\f51\fs20\ql candidate and the initiation of clinical development. Given the level of uncertainty of our ability to successfully\plain\cf1\f51\fs20\ql achieve these many steps and the uncertainty of the drug discovery and clinical development processes in general,\plain\cf1\f51\fs20\ql there can be no assurance that we will succeed in developing any marketable products as a result of our efforts with\plain\cf1\f51\fs20\ql respect to our nucleic acid chemistry technology program.\plain\cf13\f51\fs20\b\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary\plain\cf1\f51\fs20\b\i\qj regulatory approvals could be delayed or prevented.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We may not be able to initiate or continue clinical trials for our drug candidates if we are unable to locate\plain\cf1\f51\fs20\ql and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar\plain\cf1\f51\fs20\ql regulatory authorities outside the United States. For example, in September 2016, we suspended our clinical trial of\plain\cf1\f51\fs20\ql IMO-8400 in patients with DLBCL harboring the MYD88 L265P oncogenic mutation due to difficulty in enrolling\plain\cf1\f51\fs20\ql patients. Additionally, because there are a limited number of patients with dermatomyositis, or other rare diseases\plain\cf1\f51\fs20\ql having indications for which we may determine to develop our TLR antagonists, our ability to enroll eligible\plain\cf1\f51\fs20\ql patients in any clinical trials for these indications may be limited or may result in slower enrollment than we\plain\cf1\f51\fs20\ql anticipated. In addition, some of our competitors have ongoing clinical trials for drug candidates that treat the same\plain\cf1\f51\fs20\ql indications as our drug candidates, and patients who would otherwise be eligible for our clinical trials may instead\plain\cf1\f51\fs20\ql enroll in clinical trials of our competitors' drug candidates.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sa132\fi528\cf1\f51\fs20\ql Patient enrollment is affected by other factors including the:
\par\pard\plain
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh360\row}}}\pard\plain\fi528\cf1\f51\fs20\ql Our inability to enroll a sufficient number of patients for our clinical trials would result in significant delays\plain\cf1\f51\fs20\ql and could require us to abandon one or more clinical trials altogether. Enrollment delays in our clinical trials may\plain\cf1\f51\fs20\ql result in increased development costs for our drug candidates, which would cause the value of our company to\plain\cf1\f51\fs20\ql decline and limit our ability to obtain additional financing.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj If our clinical trials are unsuccessful, or if they are delayed or terminated, we may not be able to develop and\plain\cf1\f51\fs20\b\i\qj commercialize our drug candidates.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql In order to obtain regulatory approvals for the commercial sale of our drug candidates, we are required to\plain\cf1\f51\fs20\ql complete extensive clinical trials in humans to demonstrate the safety and efficacy of our drug candidates. Clinical\plain\cf1\f51\fs20\ql trials are lengthy, complex, and expensive processes with uncertain results. We may not be able to complete any\plain\cf1\f51\fs20\ql clinical trial of a potential product within any specified time period. Moreover, clinical trials may not show our\plain\cf1\f51\fs20\ql potential products to be both safe and efficacious. The FDA or other equivalent foreign regulatory agencies may not\plain\cf1\f51\fs20\ql allow us to complete these trials or commence and complete any other clinical trials.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql The results from preclinical testing of a drug candidate that is under development may not be predictive of\plain\cf1\f51\fs20\ql results that will be obtained in human clinical trials. In addition, the results of early human clinical trials may not\plain\cf1\f51\fs20\ql be predictive of results that will be obtained in larger scale, advanced stage clinical trials.\~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 36\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql Furthermore, interim results of a clinical trial do not necessarily predict final results, and failure of any of our\plain\cf1\f51\fs20\ql clinical trials can occur at any stage of testing. Companies in the biotechnology and pharmaceutical industries,\plain\cf1\f51\fs20\ql including companies with greater experience in preclinical testing and clinical trials than we have, have suffered\plain\cf1\f51\fs20\ql significant setbacks in clinical trials, even after demonstrating promising results in earlier trials. Moreover, effects\plain\cf1\f51\fs20\ql seen in nonclinical studies, even if not observed in clinical trials, may result in limitations or restrictions on clinical\plain\cf1\f51\fs20\ql trials. Numerous unforeseen events may occur during, or as a result of, preclinical testing, nonclinical testing or the\plain\cf1\f51\fs20\ql clinical trial process that could delay or inhibit the ability to receive regulatory approval or to commercialize drug\plain\cf1\f51\fs20\ql products.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Other companies developing drugs targeted to TLRs have experienced setbacks in clinical trials. These\plain\cf1\f51\fs20\ql setbacks may result in enhanced scrutiny by regulators or institutional review boards, or IRBs, of clinical trials of\plain\cf1\f51\fs20\ql our drug candidates, including our TLR-targeted drug candidates, which could result in regulators or IRBs\plain\cf1\f51\fs20\ql prohibiting the commencement of clinical trials, requiring additional nonclinical studies as a precondition to\plain\cf1\f51\fs20\ql commencing clinical trials or imposing restrictions on the design or scope of clinical trials that could slow\plain\cf1\f51\fs20\ql enrollment of trials, increase the costs of trials or limit the significance of the results of trials. Such setbacks could\plain\cf1\f51\fs20\ql also adversely impact the desire of investigators to enroll patients in, and the desire of patients to enroll in, clinical\plain\cf1\f51\fs20\ql trials of our drug candidates.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sa132\fi594\cf1\f51\fs20\ql Other events that could delay or inhibit conduct of our clinical trials include:
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql nonclinical or clinical data may not be readily interpreted, which may lead to delays and/or\plain\intbl\sa132\cf1\f51\fs20\ql misinterpretation;\cell{
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\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our nonclinical tests, including toxicology studies, or clinical trials may produce negative or inconclusive\plain\intbl\cf1\f51\fs20\ql results, and we may decide, or regulators may require us, to conduct additional nonclinical testing or\plain\intbl\sa132\cf1\f51\fs20\ql clinical trials or we may abandon projects that we expect may not be promising;\cell{
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\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql the rate of enrollment or retention of patients in our clinical trials may be lower than we expect;\cell{
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\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we might have to suspend or terminate our clinical trials if the participating subjects experience serious\plain\intbl\sa132\cf1\f51\fs20\ql adverse events or undesirable side effects or are exposed to unacceptable health risks;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql regulators or IRBs may hold, suspend or terminate clinical research for various reasons, including\plain\intbl\cf1\f51\fs20\ql noncompliance with regulatory requirements, issues identified through inspections of manufacturing or\plain\intbl\cf1\f51\fs20\ql clinical trial operations or clinical trial sites, or if, in their opinion, the participating subjects are being\plain\intbl\sa132\cf1\f51\fs20\ql exposed to unacceptable health risks;\cell{
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql regulators may hold or suspend our clinical trials while collecting supplemental information on,\plain\intbl\cf1\f51\fs20\ql or clarification of, our clinical trials or other clinical trials, including trials conducted in other\plain\intbl\sa132\cf1\f51\fs20\ql countries or trials conducted by other companies;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we, along with our collaborators and subcontractors, may not employ, in any capacity, persons who have\plain\intbl\cf1\f51\fs20\ql been debarred under the FDA's Application Integrity Policy, or similar policy under foreign regulatory\plain\intbl\cf1\f51\fs20\ql authorities. Employment of such debarred persons, even if inadvertent, may result in delays in the FDA's\plain\intbl\cf1\f51\fs20\ql or foreign equivalent's review or approval of our drug candidates, or the rejection of data developed with\plain\intbl\sa132\cf1\f51\fs20\ql the involvement of such person(s);\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we or our contract manufacturers may be unable to manufacture sufficient quantities of our drug\plain\intbl\sa132\cf1\f51\fs20\ql candidates for use in clinical trials;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the cost of our clinical trials may be greater than we currently anticipate making continuation and/or\plain\intbl\sa132\cf1\f51\fs20\ql completion improbable; and\cell{
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our drug candidates may not cause the desired effects or may cause undesirable side effects or our drug\plain\intbl\cf1\f51\fs20\ql candidates may have other unexpected characteristics.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\ql We do not know whether clinical trials will begin as planned, will need to be restructured or will be\plain\cf1\f51\fs20\ql completed on schedule, if at all. Significant clinical trial delays also could allow our competitors to bring products\plain\cf1\f51\fs20\ql to market before we do and impair our ability to commercialize our drug candidates.\par\pard\plain\sb528\cf1\f51\fs20\qc 37\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Delays in commencing clinical trials of potential products could increase our costs, delay any potential revenues,\plain\cf1\f51\fs20\b\i\qj and reduce the probability that a potential product will receive regulatory approval.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our drug candidates and our collaborators' drug candidates will require preclinical and other nonclinical\plain\cf1\f51\fs20\ql testing and extensive clinical trials prior to submission of any regulatory application for commercial sales. In\plain\cf1\f51\fs20\ql conducting clinical trials, we cannot be certain that any planned clinical trial will begin on time, if at all. Delays in\plain\cf1\f51\fs20\ql commencing clinical trials of potential products could increase our drug candidate development costs, delay any\plain\cf1\f51\fs20\ql potential revenues, reduce the potential length of patent exclusivity and reduce the probability that a potential\plain\cf1\f51\fs20\ql product will receive regulatory approval.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sa132\fi528\cf1\f51\fs20\ql Commencing clinical trials may be delayed for a number of reasons, including delays in:
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql manufacturing sufficient quantities of drug candidate that satisfy the required quality standards for use in\plain\intbl\sa132\cf1\f51\fs20\ql clinical trials;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql demonstrating sufficient safety to obtain regulatory approval for conducting a clinical trial;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql reaching an agreement with any collaborators on all aspects of the clinical trial;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql reaching agreement with contract research organizations, if any, and clinical trial sites on all aspects of\plain\intbl\sa132\cf1\f51\fs20\ql the clinical trial;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql resolving any objections from the FDA or any regulatory authority on an IND or proposed clinical trial\plain\intbl\sa132\cf1\f51\fs20\ql design; \~\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql obtaining additional financing;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql obtaining IRB approval for conducting a clinical trial at a prospective site; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql enrolling patients in order to commence the clinical trial.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj The technologies on which we rely are unproven and may not result in any approved and marketable products.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our technologies or therapeutic approaches are relatively new and unproven. We have focused our efforts on\plain\cf1\f51\fs20\ql the research and development of RNA- and DNA-based compounds, or oligonucleotides, targeted to TLRs and on\plain\cf1\f51\fs20\ql drug candidates using our nucleic acid technology. Neither we nor any other company have obtained regulatory\plain\cf1\f51\fs20\ql approval to market such TLR-targeted drug candidates or drug candidates using our nucleic acid technology as\plain\cf1\f51\fs20\ql therapeutic drugs, and no such products currently are being marketed. The results of preclinical studies with\plain\cf1\f51\fs20\ql TLR-targeted compounds may not be indicative of results that may be obtained in clinical trials, and results we\plain\cf1\f51\fs20\ql have obtained in the clinical trials we have conducted to date may not be predictive of results in subsequent\plain\cf1\f51\fs20\ql large-scale clinical trials. Further, the chemical and pharmacological properties of RNA- and DNA-based\plain\cf1\f51\fs20\ql compounds targeted to TLRs or of drug candidates using our nucleic acid technology may not be fully recognized\plain\cf1\f51\fs20\ql in preclinical studies and small-scale clinical trials, and such compounds may interact with human biological\plain\cf1\f51\fs20\ql systems in unforeseen, ineffective or harmful ways that we have not yet identified.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Moreover, only five nucleic acid-based therapeutics have been approved by the FDA for marketing in the\plain\cf1\f51\fs20\ql United States since 1998 and are currently being marketed.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql As such, oligonucleotides as a chemical class of drug candidates have limited precedence for successful\plain\cf1\f51\fs20\ql late-stage development and regulatory approval. As we progress our oligonucleotide drug candidates into Phase 2\plain\cf1\f51\fs20\ql clinical trials involving patients with severe disease and as we conduct long-term nonclinical toxicology studies, we\plain\cf1\f51\fs20\ql expect to encounter an increased risk of generating clinical adverse events and nonclinical toxicology study results\plain\cf1\f51\fs20\ql that will require careful interpretation. In animal toxicology studies, we have observed adverse treatment-related\plain\cf1\f51\fs20\ql effects on serum complement as well as evidence of adverse kidney, vascular, and heart pathology in longer term\plain\cf1\f51\fs20\ql dosing of animals with our oligonucleotide compounds, which we believe are consistent with data previously\plain\cf1\f51\fs20\ql generated with other third party oligonucleotides. Given the limited experience in assessing the relevance of\plain\cf1\f51\fs20\ql oligonucleotide-related adverse animal toxicology findings to humans, the clinical and regulatory context for\plain\cf1\f51\fs20\ql interpreting the significance of such events and results is not well established.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 38\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql As a result of these factors, we may never succeed in obtaining regulatory approval to market any product.\plain\cf1\f51\fs20\ql Furthermore, the commercial success of any of our drug candidates for which we may obtain marketing approval\plain\cf1\f51\fs20\ql from the FDA or other regulatory authorities will depend upon their acceptance by patients, the medical community,\plain\cf1\f51\fs20\ql and third-party payors as clinically useful, safe, and cost-effective. In addition, if products being developed by our\plain\cf1\f51\fs20\ql competitors have negative clinical trial results or otherwise are viewed negatively, the perception of our technologies\plain\cf1\f51\fs20\ql and market acceptance of our drug candidates could be impacted negatively.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our setbacks with respect to our TLR-targeted compounds, together with the setbacks experienced by other\plain\cf1\f51\fs20\ql companies developing oligonucleotides-based compounds and TLR-targeted compounds, may result in a negative\plain\cf1\f51\fs20\ql perception of our technology and our TLR-targeted compounds, impact our ability to obtain marketing approval of\plain\cf1\f51\fs20\ql these drug candidates and adversely affect acceptance of our technology and our TLR-targeted compounds by\plain\cf1\f51\fs20\ql patients, the medical community and third-party payors.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our efforts to educate the medical community on our potentially unique approaches may require greater\plain\cf1\f51\fs20\ql resources than would be typically required for products based on conventional technologies or therapeutic\plain\cf1\f51\fs20\ql approaches. The safety, efficacy, convenience, and cost-effectiveness of our drug candidates as compared to\plain\cf1\f51\fs20\ql competitive products will also affect market acceptance.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We face substantial competition, which may result in others discovering, developing or commercializing drugs\plain\cf1\f51\fs20\b\i\qj before or more successfully than us.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We are developing our TLR-targeted drug candidates for use in{\*\bkmkstart _cp_text_1_435_12112272}{\*\bkmkend _cp_text_1_435_12112272}\plain\cf1\f51\fs20\ql our immuno-oncology program and in the\plain\cf1\f51\fs20\ql treatment of certain rare diseases{\*\bkmkstart _cp_text_1_441_12112272}{\*\bkmkend _cp_text_1_441_12112272}\plain\cf1\f51\fs20\ql . We are conducting a Phase 1/2 clinical trial of IMO-2125, administered\plain\cf1\f51\fs20\ql intra-tumorally, in combination with ipilimumab, a CTLA4 antibody, or pembrolizumab in patients with metastatic\plain\cf1\f51\fs20\ql melanoma and plan to initiate additional clinical trials of IMO-2125 in our immuno-oncology program both as a\plain\cf1\f51\fs20\ql monotherapy and in combination with checkpoint inhibitors for the treatment of multiple tumor types. We{\*\bkmkstart _cp_text_4_442_12112272}{\*\bkmkend _cp_text_4_442_12112272}\plain\cf1\f51\fs20\ql are\plain\cf1\f51\fs20\ql conducting a Phase 2 clinical trial of IMO-8400 in patients with dermatomyositis{\*\bkmkstart _cp_text_1_443_12112272}{\*\bkmkend _cp_text_1_443_12112272}\plain\cf1\f51\fs20\ql . We also entered into a\plain\cf1\f51\fs20\ql collaborative alliance agreement with GSK, and expect to seek to enter into additional collaborative alliances with\plain\cf1\f51\fs20\ql pharmaceutical companies with respect to applications of our nucleic acid chemistry technology research program.\plain\cf1\f51\fs20\ql For all of these disease areas, there are many other companies, public and private, that are actively engaged in\plain\cf1\f51\fs20\ql discovery, development, and commercializing products and technologies that may compete with our drug candidates\plain\cf1\f51\fs20\ql and programs, including TLR-targeted compounds as well as non-TLR-targeted therapeutics.\plain\cf13\f51\fs20\b\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql We are aware of other companies including Dynavax Technologies Corporation, Mologen AG, BioLineRx\plain\cf1\f51\fs20\ql Ltd., Innate Immunotherapeutics Ltd., VentiRx Pharmaceuticals Inc., Telormedix S.A., Gilead Sciences Inc.,\plain\cf1\f51\fs20\ql GlaxoSmithKline plc, AstraZeneca plc, Checkmate Pharmaceuticals, Inc. and Hoffmann-La Roche Ltd. that are\plain\cf1\f51\fs20\ql developing TLR agonists and antagonists for various indications, including oncology and rare diseases.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Immuno-oncology, which utilizes a patient's own immune system to combat cancer, is currently an active area\plain\cf1\f51\fs20\ql of research for biotechnology and pharmaceutical companies. Interest in immuno-oncology is driven by recent\plain\cf1\f51\fs20\ql efficacy data in cancers with historically bleak outcomes and the potential to achieve a cure or functional cure for\plain\cf1\f51\fs20\ql some patients. As such, our efforts in this field will be competitive with a wide variety of different approaches. Any\plain\cf1\f51\fs20\ql one of these competitive approaches may result in the development of novel technologies that are more effective,\plain\cf1\f51\fs20\ql safer or less costly than any that we are developing. In addition, Dynavax is conducting a Phase 1/2 clinical trial of\plain\cf1\f51\fs20\ql an investigational TLR9 agonist in combination with checkpoint inhibitors and Checkmate is conducting a Phase 1b\plain\cf1\f51\fs20\ql clinical trial of an investigational TLR9 agonist in combination with a checkpoint inhibitor.\par\pard\plain\fi528\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_4_445_12112272}{\*\bkmkend _cp_text_4_445_12112272}\par\pard\plain\fi528\cf1\f51\fs20\ql Many of the drug development programs in dermatomyositis are focusing on expanding the use of drugs\plain\cf1\f51\fs20\ql approved in different indications through investigator sponsored studies such as the ongoing studies of the\plain\cf1\f51\fs20\ql monoclonal antibodies, belimumab and tocilizumab. We are not aware of other new chemical or molecular entities\plain\cf1\f51\fs20\ql being developed for the treatment of dermatomyositis.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We are also developing nucleic acid chemistry drug candidates that we have created using our proprietary\plain\cf1\f51\fs20\ql technology to inhibit the production of disease-associated proteins by targeting RNA. We also face competition\plain\cf1\f51\fs20\ql from other companies working to develop novel drugs using technologies that may compete with our nucleic acid\plain\cf1\f51\fs20\ql chemistry technology. We are aware of multiple companies that are developing technologies that use\plain\cf1\f51\fs20\ql oligonucleotide-based compounds to inhibit the production of disease associated proteins. These technologies\plain\cf1\f51\fs20\ql include, but are not limited to, antisense technology as well as RNAi. In the field of antisense technologies, we\par\pard\plain\sb528\cf1\f51\fs20\qc 39\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql compete with multiple companies, including Ionis and its partners, as well as WAVE Life Sciences and its partner.\plain\cf1\f51\fs20\ql Ionis is currently marketing an antisense drug, Kynamro, and Biogen recently received FDA approval for its\plain\cf1\f51\fs20\ql antisense drug Spinraza for spinal muscular atrophy.\~\~Ionis has over two dozen antisense drug candidates in clinical\plain\cf1\f51\fs20\ql trials. In the field of RNAi, our primary competition is with Alnylam, Dicerna, Miragen, and their respective\plain\cf1\f51\fs20\ql partners. For example, Alnylam is developing multiple RNAi-based technologies and has six drug candidates in\plain\cf1\f51\fs20\ql clinical trials. Any of the competing companies may develop gene-silencing technologies more rapidly and more\plain\cf1\f51\fs20\ql effectively than us, and antisense technology and RNAi may become the preferred technology for drugs that target\plain\cf1\f51\fs20\ql RNA in order to inhibit the production of disease-associated proteins.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Some of these potentially competitive products have been in development or commercialized for years, in\plain\cf1\f51\fs20\ql some cases by large, well established pharmaceutical companies. Many of the marketed products have been\plain\cf1\f51\fs20\ql accepted by the medical community, patients, and third-party payors. Our ability to compete may be affected by the\plain\cf1\f51\fs20\ql previous adoption of such products by the medical community, patients, and third-party payors. Additionally, in\plain\cf1\f51\fs20\ql some instances, insurers and other third-party payors seek to encourage the use of generic products, which makes\plain\cf1\f51\fs20\ql branded products, such as is planned for our drug candidates upon commercialization, potentially less attractive,\plain\cf1\f51\fs20\ql from a cost perspective, to buyers.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We recognize that other companies, including large pharmaceutical companies, may be developing or have\plain\cf1\f51\fs20\ql plans to develop products and technologies that may compete with ours. Many of our competitors have substantially\plain\cf1\f51\fs20\ql greater financial, technical, and human resources than we have. In addition, many of our competitors have\plain\cf1\f51\fs20\ql significantly greater experience than we have in undertaking preclinical studies and human clinical trials of new\plain\cf1\f51\fs20\ql pharmaceutical products, obtaining FDA and other regulatory approvals of products for use in health care and\plain\cf1\f51\fs20\ql manufacturing, and marketing and selling approved products. Our competitors may discover, develop or\plain\cf1\f51\fs20\ql commercialize products or other novel technologies that are more effective, safer or less costly than any that we are\plain\cf1\f51\fs20\ql developing. Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than\plain\cf1\f51\fs20\ql we may obtain approval for ours.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We anticipate that the competition with our drug candidates and technologies will be based on a number of\plain\cf1\f51\fs20\ql factors including product efficacy, safety, availability, and price. The timing of market introduction of our drug\plain\cf1\f51\fs20\ql candidates and competitive products will also affect competition among products. We expect the relative speed with\plain\cf1\f51\fs20\ql which we can develop products, complete the clinical trials and approval processes, and supply commercial\plain\cf1\f51\fs20\ql quantities of the products to the market to be important competitive factors. Our competitive position will also\plain\cf1\f51\fs20\ql depend upon our ability to attract and retain qualified personnel, to obtain patent protection or otherwise develop\plain\cf1\f51\fs20\ql proprietary products or processes, protect our intellectual property, and to secure sufficient capital resources for the\plain\cf1\f51\fs20\ql period between technological conception and commercial sales.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Competition for technical and management personnel is intense in our industry, and we may not be able to\plain\cf1\f51\fs20\b\i\qj sustain our operations or grow if we are unable to attract and retain key personnel.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our success is highly dependent on the retention of principal members of our technical and management staff,\plain\cf1\f51\fs20\ql including our President and Chief Executive Officer, Mr. Vincent Milano.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We are a party to{\*\bkmkstart _cp_text_1_451_12112272}{\*\bkmkend _cp_text_1_451_12112272}\plain\cf1\f51\fs20\ql an employment agreement with Mr. Milano{\*\bkmkstart _cp_text_1_455_12112272}{\*\bkmkend _cp_text_1_455_12112272}\plain\cf1\f51\fs20\ql , which is terminable upon 15 days prior written\plain\cf1\f51\fs20\ql notice at the election of either party and immediately in the event of a termination for cause (as defined therein).\plain\cf1\f51\fs20\ql We do not carry key man life insurance for Mr. Milano.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Furthermore, our future growth will require hiring a number of qualified technical and management personnel.\plain\cf1\f51\fs20\ql Accordingly, recruiting and retaining such personnel in the future will be critical to our success. There is intense\plain\cf1\f51\fs20\ql competition from other companies and research and academic institutions for qualified personnel in the areas of our\plain\cf1\f51\fs20\ql activities. If we are not able to continue to attract and retain, on acceptable terms, the qualified personnel necessary\plain\cf1\f51\fs20\ql for the continued development of our business, we may not be able to sustain our operations or growth.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_318_12112272}{\*\bkmkend _cp_text_1_318_12112272}\par\pard\plain\sb528\cf1\f51\fs20\qc 40\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\qc Risks Related to Regulatory Approval and Marketing of Our Drug Candidates and Other\par\pard\plain\cf1\f51\fs20\b\qc Legal Compliance Matters\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj Even if we complete the necessary preclinical studies and clinical trials, the marketing approval process is\plain\cf1\f51\fs20\b\i\qj expensive, time-consuming and uncertain and may prevent us from obtaining approvals for the\plain\cf1\f51\fs20\b\i\qj commercialization of some or all of our drug candidates. As a result, we cannot predict when or if we, or any\plain\cf1\f51\fs20\b\i\qj future collaborators, will obtain marketing approval to commercialize a drug candidate.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our drug candidates and the activities associated with their development and commercialization, including\plain\cf1\f51\fs20\ql their design, testing, manufacture, safety, efficacy, recordkeeping, labeling, storage, approval, marketing, promotion,\plain\cf1\f51\fs20\ql sale and distribution, export and import are subject to extensive regulation by the FDA and comparable foreign\plain\cf1\f51\fs20\ql regulatory authorities, whose laws and regulations may differ from country to country. We are not permitted to\plain\cf1\f51\fs20\ql market our drug candidates in the United States or in other countries until we, or any future collaborators, receive\plain\cf1\f51\fs20\ql approval of an NDA from the FDA or marketing approval from applicable regulatory authorities outside of the\plain\cf1\f51\fs20\ql United States.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql All of the drug candidates that we are developing, or may develop in the future, will require additional\plain\cf1\f51\fs20\ql research and development, extensive preclinical studies, nonclinical testing, clinical trials, and regulatory approval\plain\cf1\f51\fs20\ql prior to any commercial sales. This process is lengthy, often taking a number of years, is uncertain, and is\plain\cf1\f51\fs20\ql expensive. Securing marketing approval requires the submission of extensive preclinical and clinical data and\plain\cf1\f51\fs20\ql supporting information to regulatory authorities for each therapeutic indication to establish the drug candidate's\plain\cf1\f51\fs20\ql safety and purity. Securing marketing approval also requires the submission of information about the product\plain\cf1\f51\fs20\ql manufacturing process to, and inspection of manufacturing facilities by, the regulatory authorities.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Since our inception, we have conducted clinical trials of a number of compounds and are planning to initiate\plain\sa132\cf1\f51\fs20\ql clinical trials for a number of additional disease indications. Specifically:
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we are conducting a Phase 1/2 clinical trial of IMO-2125, administered intra-tumorally, in combination\plain\intbl\cf1\f51\fs20\ql with ipilimumab or pembrolizumab in patients with anti-PD1 refractory metastatic melanoma{\*\bkmkstart _cp_text_1_460_12112272}{\*\bkmkend _cp_text_1_460_12112272}\plain\intbl\cf1\f51\fs20\ql , a Phase 3\plain\intbl\cf1\f51\fs20\ql clinical trial of IMO-2125, administered intra-tumorally, in combination with ipilimumab in patients\plain\intbl\cf1\f51\fs20\ql with anti-PD1 refractory metastatic melanoma, and a Phase 1b trial of IMO-2125 administered\plain\intbl\cf1\f51\fs20\ql intra-tumorally,{\*\bkmkstart _cp_text_4_461_12112272}{\*\bkmkend _cp_text_4_461_12112272}\plain\intbl\cf1\f51\fs20\ql as a monotherapy{\*\bkmkstart _cp_text_1_462_12112272}{\*\bkmkend _cp_text_1_462_12112272}\plain\intbl\sa132\cf1\f51\fs20\ql in patients with refractory solid tumors; \~\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we may conduct additional clinical trials of IMO-2125 in our immuno-oncology program and in\plain\intbl\sa132\cf1\f51\fs20\ql combination with checkpoint inhibitors for the treatment of multiple tumor types;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we are conducting a Phase 2 clinical trial of IMO-8400 in patients with dermatomyositis;\plain\intbl\sa132\cf1\f51\fs20\ql and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh742
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql we are developing compounds in our nucleic acid chemistry research program and{\*\bkmkstart _cp_text_1_467_12112272}{\*\bkmkend _cp_text_1_467_12112272}\plain\intbl\cf1\f51\fs20\ql plan to make a\plain\intbl\cf1\f51\fs20\ql development decision for IDRA-008 based upon the totality of IND-enabling studies and our comparator\plain\intbl\cf1\f51\fs20\ql pharmacology study with Volanesorsen.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh742\row}}}\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FDA and other regulatory authorities may not approve any of our potential products for any indication.\par\pard\plain\fi594\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\qj We may need to address a number of technological challenges in order to complete development of our drug\plain\cf1\f51\fs20\qj candidates. Moreover, these products may not be effective in treating any disease or may prove to have undesirable\plain\cf1\f51\fs20\qj or unintended side effects, unintended alteration of the immune system over time, toxicities or other characteristics\plain\cf1\f51\fs20\qj that may preclude our obtaining regulatory approval or prevent or limit commercial use. In addition, changes in\plain\cf1\f51\fs20\qj marketing approval policies during the development period, changes in or the enactment of additional statutes or\plain\cf1\f51\fs20\qj regulations, or changes in regulatory review for each submitted product application, may cause delays in the\plain\cf1\f51\fs20\qj approval or rejection of an application. The FDA and comparable authorities in other countries have substantial\plain\cf1\f51\fs20\qj discretion in the approval process and may refuse to accept any application or may decide that our data is\plain\cf1\f51\fs20\qj insufficient for approval and require additional preclinical, clinical or other studies. In addition, varying\plain\cf1\f51\fs20\qj interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing\plain\cf1\f51\fs20\qj approval of a drug candidate.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql Any delay in obtaining or failure to obtain required approvals could materially adversely affect our ability or\plain\cf1\f51\fs20\ql that of any collaborators we may have to generate revenue from the particular drug candidate, which likely would\plain\cf1\f51\fs20\ql result in significant harm to our financial position and adversely impact our stock price.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 41\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\i\qj Our failure to obtain marketing approval in foreign jurisdictions would prevent our drug candidates from being\plain\cf1\f51\fs20\b\i\qj marketed abroad, and any approval we are granted for our drug candidates in the United States would not\plain\cf1\f51\fs20\b\i\qj assure approval of drug candidates in foreign jurisdictions.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In order to market and sell our drugs in the European Union and many other jurisdictions, we, and any future\plain\cf1\f51\fs20\ql collaborators, must obtain separate marketing approvals and comply with numerous and varying regulatory\plain\cf1\f51\fs20\ql requirements. The approval procedure varies among countries and can involve additional testing. The time required\plain\cf1\f51\fs20\ql to obtain approval may differ substantially from that required to obtain FDA approval. The marketing approval\plain\cf1\f51\fs20\ql process outside of the United States generally includes all of the risks associated with obtaining FDA approval. In\plain\cf1\f51\fs20\ql addition, in many countries outside of the United States, it is required that the drug be approved for reimbursement\plain\cf1\f51\fs20\ql before the drug can be approved for sale in that country. We, and any future collaborators, may not obtain\plain\cf1\f51\fs20\ql approvals from regulatory authorities outside of the United States on a timely basis, if at all. Approval by the FDA\plain\cf1\f51\fs20\ql does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory\plain\cf1\f51\fs20\ql authority outside of the United States does not ensure approval by regulatory authorities in other countries or\plain\cf1\f51\fs20\ql jurisdictions or by the FDA.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Additionally, on June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European\plain\cf1\f51\fs20\ql Union, commonly referred to as Brexit. On March 29, 2017, the country formally notified the European Union of\plain\cf1\f51\fs20\ql its intention to withdraw pursuant to Article 50 of the Lisbon Treaty. Since a significant proportion of the regulatory\plain\cf1\f51\fs20\ql framework in the United Kingdom is derived from European Union directives and regulations, the referendum could\plain\cf1\f51\fs20\ql materially impact the regulatory regime with respect to the approval of our drug candidates in the United Kingdom\plain\cf1\f51\fs20\ql or the European Union. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of\plain\cf1\f51\fs20\ql Brexit or otherwise, would prevent us from commercializing our drug candidates in the United Kingdom and/or the\plain\cf1\f51\fs20\ql European Union and restrict our ability to generate revenue and achieve and sustain profitability. If any of these\plain\cf1\f51\fs20\ql outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom\plain\cf1\f51\fs20\ql and/or European Union for our drug candidates, which could significantly and materially harm our business.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Even if we, or any future collaborators, obtain marketing approvals for our drug candidates, the terms of\plain\cf1\f51\fs20\b\i\qj approvals and ongoing regulation of our drugs may limit how we, or they, manufacture and market our drugs,\plain\cf1\f51\fs20\b\i\qj which could materially impair our ability to generate revenue.\par\pard\plain\cf1\f51\fs24\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Once marketing approval has been granted, an approved drug and its manufacturer and marketer are subject\plain\cf1\f51\fs20\ql to ongoing review and extensive regulation. We, and any future collaborators, must therefore comply with\plain\cf1\f51\fs20\ql requirements concerning advertising and promotion for any of our drug candidates for which we or they obtain\plain\cf1\f51\fs20\ql marketing approval. Promotional communications with respect to prescription drugs are subject to a variety of legal\plain\cf1\f51\fs20\ql and regulatory restrictions and must be consistent with the information in the drug\u8217?s approved labeling. Thus,\plain\cf1\f51\fs20\ql we, and any future collaborators, may not be able to promote any drugs we develop for indications or uses for\plain\cf1\f51\fs20\ql which they are not approved.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql In addition, manufacturers of approved drugs and those manufacturers\u8217? facilities are required to\plain\cf1\f51\fs20\ql comply with extensive FDA requirements, including ensuring that quality control and manufacturing procedures\plain\cf1\f51\fs20\ql conform to cGMPs, which include requirements relating to quality control and quality assurance as well as the\plain\cf1\f51\fs20\ql corresponding maintenance of records and documentation and reporting requirements. We, our contract\plain\cf1\f51\fs20\ql manufacturers, our future collaborators and their contract manufacturers could be subject to periodic unannounced\plain\cf1\f51\fs20\ql inspections by the FDA to monitor and ensure compliance with cGMPs.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql Accordingly, assuming we, or our future collaborators, receive marketing approval for one or more of our\plain\cf1\f51\fs20\ql drug candidates, we, and our future collaborators, and our and their contract manufacturers will continue to expend\plain\cf1\f51\fs20\ql time, money and effort in all areas of regulatory compliance, including manufacturing, production, product\plain\cf1\f51\fs20\ql surveillance and quality control.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql If we, and our future collaborators, are not able to comply with post-approval regulatory requirements, we,\plain\cf1\f51\fs20\ql and our future collaborators, could have the marketing approvals for our drugs withdrawn by regulatory authorities\plain\cf1\f51\fs20\ql and our, or our future collaborators\u8217?, ability to market any future drugs could be limited, which could\plain\cf1\f51\fs20\ql adversely affect our ability to achieve or sustain profitability. Further, the cost of compliance with post-approval\plain\cf1\f51\fs20\ql regulations may have a negative effect on our operating results and financial condition.\par\pard\plain\fi528\cf1\f51\fs20\qj \~\par\pard\plain\sb528\cf1\f51\fs20\qc 42\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\qj Moreover, legislative and regulatory proposals have been made to expand post-approval requirements and\plain\cf1\f51\fs20\qj restrict sales and promotional activities for pharmaceutical products. We cannot be sure whether additional\plain\cf1\f51\fs20\qj legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or\plain\cf1\f51\fs20\qj what the impact of such changes on the marketing approvals of our drug candidates, if any, may be. In addition,\plain\cf1\f51\fs20\qj increased scrutiny by the United States Congress of the FDA's approval process may significantly delay or prevent\plain\cf1\f51\fs20\qj marketing approval, as well as subject us and any collaborators to more stringent product labeling and\plain\cf1\f51\fs20\qj post-marketing testing and other requirements.\par\pard\plain\cf1\f51\fs24\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj Any of our drug candidates for which we, or our future collaborators, obtain marketing approval in the future\plain\cf1\f51\fs20\b\i\qj could be subject to post-marketing restrictions or withdrawal from the market and we, and our future\plain\cf1\f51\fs20\b\i\qj collaborators, may be subject to substantial penalties if we, or they, fail to comply with regulatory requirements\plain\cf1\f51\fs20\b\i\qj or if we, or they, experience unanticipated problems with our drugs following approval.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql Any of our drug candidates for which we, or our future collaborators, obtain marketing approval in the future,\plain\cf1\f51\fs20\ql as well as the manufacturing processes, post-approval studies and measures, labeling, advertising and promotional\plain\cf1\f51\fs20\ql activities for such drug, among other things, will be subject to continual requirements of and review by the FDA\plain\cf1\f51\fs20\ql and other regulatory authorities. These requirements include submissions of safety and other post-marketing\plain\cf1\f51\fs20\ql information and reports, registration and listing requirements, requirements relating to manufacturing, quality\plain\cf1\f51\fs20\ql control, quality assurance and corresponding maintenance of records and documents, requirements regarding the\plain\cf1\f51\fs20\ql distribution of samples to physicians and recordkeeping. Even if marketing approval of a drug candidate is granted,\plain\cf1\f51\fs20\ql the approval may be subject to limitations on the indicated uses for which the drug may be marketed or to the\plain\cf1\f51\fs20\ql conditions of approval, including the requirement to implement a Risk Evaluation and Mitigation Strategy, which\plain\cf1\f51\fs20\ql could include requirements for a restricted distribution system.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance\plain\cf1\f51\fs20\ql to monitor the safety or efficacy of a drug. The FDA and other agencies, including the Department of Justice, or the\plain\cf1\f51\fs20\ql DOJ, closely regulate and monitor the post-approval marketing and promotion of drugs to ensure that they are\plain\cf1\f51\fs20\ql manufactured, marketed and distributed only for the approved indications and in accordance with the provisions of\plain\cf1\f51\fs20\ql the approved labeling. The FDA imposes stringent restrictions on manufacturers\u8217? communications regarding\plain\cf1\f51\fs20\ql off-label use and if we, or our future collaborators, do not market any of our drug candidates for which we, or\plain\cf1\f51\fs20\ql they, receive marketing approval for only their approved indications, we, or they, may be subject to warnings or\plain\cf1\f51\fs20\ql enforcement action for off-label marketing. Violation of the FDCA and other statutes, including the False Claims\plain\cf1\f51\fs20\ql Act, relating to the promotion and advertising of prescription drugs may lead to investigations or allegations of\plain\cf1\f51\fs20\ql violations of federal and state health care fraud and abuse laws and state consumer protection laws.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql In addition, later discovery of previously unknown adverse events or other problems with our drugs or their\plain\cf1\f51\fs20\ql manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various\plain\cf1\f51\fs20\ql results, including:\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?litigation involving patients taking our drug;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~restrictions on such drugs, manufacturers or manufacturing processes;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~restrictions on the labeling or marketing of a drug;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?restrictions on drug distribution or use;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~requirements to conduct post-marketing studies or clinical trials;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~warning letters or untitled letters;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?withdrawal of the drugs from the market;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~refusal to approve pending applications or supplements to approved applications that we submit;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~recall of drugs;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?fines, restitution or disgorgement of profits or revenues;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~suspension or withdrawal of marketing approvals;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?damage to relationships with any potential collaborators;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~unfavorable press coverage and damage to our reputation;\par\pard\plain\sb528\cf1\f51\fs20\qc 43\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?refusal to permit the import or export of drugs;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~drug seizure; or\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?injunctions or the imposition of civil or criminal penalties.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Under the CURES Act and the Trump Administration\u8217?s regulatory reform initiatives, the FDA\u8217?s\plain\cf1\f51\fs20\b\i\ql policies, regulations and guidance may be revised or revoked and that could prevent, limit or delay regulatory\plain\cf1\f51\fs20\b\i\ql approval of our drug candidates, which would impact our ability to generate revenue.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql In December 2016, the 21st Century Cures Act, or Cures Act, was signed into law. The Cures Act, among\plain\cf1\f51\fs20\ql other things, is intended to modernize the regulation of drugs and spur innovation, but its ultimate implementation is\plain\cf1\f51\fs20\ql unclear. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements\plain\cf1\f51\fs20\ql or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we\plain\cf1\f51\fs20\ql may have obtained and we may not achieve or sustain profitability, which would adversely affect our business,\plain\cf1\f51\fs20\ql prospects, financial condition and results of operations.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql We also cannot predict the likelihood, nature or extent of government regulation that may arise from future\plain\cf1\f51\fs20\ql legislation or administrative or executive action, either in the United States or abroad. For example, certain policies\plain\cf1\f51\fs20\ql of the Trump administration may impact our business and industry. Namely, the Trump administration has taken\plain\cf1\f51\fs20\ql several executive actions, including the issuance of a number of Executive Orders, that could impose significant\plain\cf1\f51\fs20\ql burdens on, or otherwise materially delay, the FDA\u8217?s ability to engage in routine regulatory and oversight\plain\cf1\f51\fs20\ql activities such as implementing statutes through rulemaking, issuance of guidance, and review and approval of\plain\cf1\f51\fs20\ql marketing applications. An under-staffed FDA could result in delays in the FDA\u8217?s responsiveness or in its\plain\cf1\f51\fs20\ql ability to review submissions or applications, issue regulations or guidance, or implement or enforce regulatory\plain\cf1\f51\fs20\ql requirements in a timely fashion or at all. Moreover, on January\~30, 2017, President Trump issued an Executive\plain\cf1\f51\fs20\ql Order, applicable to all executive agencies, including the FDA, which requires that for each notice of proposed\plain\cf1\f51\fs20\ql rulemaking or final regulation to be issued in fiscal year 2017, the agency shall identify at least two existing\plain\cf1\f51\fs20\ql regulations to be repealed, unless prohibited by law. These requirements are referred to as the\plain\cf1\f51\fs20\ql \u8220?two-for-one\u8221? provisions. This Executive Order includes a budget neutrality provision that requires\plain\cf1\f51\fs20\ql the total incremental cost of all new regulations in the 2017 fiscal year, including repealed regulations, to be no\plain\cf1\f51\fs20\ql greater than zero, except in limited circumstances. For fiscal years 2018 and beyond, the Executive Order requires\plain\cf1\f51\fs20\ql agencies to identify regulations to offset any incremental cost of a new regulation and approximate the total costs or\plain\cf1\f51\fs20\ql savings associated with each new regulation or repealed regulation. In interim guidance issued by the Office of\plain\cf1\f51\fs20\ql Information and Regulatory Affairs within OMB on February\~2, 2017, the administration indicates that the\plain\cf1\f51\fs20\ql \u8220?two-for-one\u8221? provisions may apply not only to agency regulations, but also to significant agency\plain\cf1\f51\fs20\ql guidance documents. In addition, on February\~24, 2017, President Trump issued an executive order directing each\plain\cf1\f51\fs20\ql affected agency to designate an agency official as a \u8220?Regulatory Reform Officer\u8221? and establish a\plain\cf1\f51\fs20\ql \u8220?Regulatory Reform Task Force\u8221? to implement the two-for-one provisions and other previously issued\plain\cf1\f51\fs20\ql executive orders relating to the review of federal regulations, however it is difficult to predict how these\plain\cf1\f51\fs20\ql requirements will be implemented, and the extent to which they will impact the FDA\u8217?s ability to exercise its\plain\cf1\f51\fs20\ql regulatory authority. If these executive actions impose constraints on the FDA\u8217?s ability to engage in oversight\plain\cf1\f51\fs20\ql and implementation activities in the normal course, our business may be negatively impacted.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj We may not be able to obtain orphan drug exclusivity for applications of our TLR drug candidates.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Regulatory authorities in some jurisdictions, including the United States and Europe, may designate drugs for\plain\cf1\f51\fs20\ql relatively small patient populations as orphan drugs. Under the Orphan Drug Act, the FDA may designate a product\plain\cf1\f51\fs20\ql as an orphan drug if it is a drug intended to treat a rare disease or condition, which is generally defined as a patient\plain\cf1\f51\fs20\ql population of fewer than 200,000 individuals in the United States.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for\plain\cf1\f51\fs20\ql the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which\plain\cf1\f51\fs20\ql precludes the European Medicines Agency, or EMA, or the FDA from approving another marketing application for\plain\cf1\f51\fs20\ql the same drug for the same indication for that exclusivity period. The applicable period is seven years in the United\plain\cf1\f51\fs20\ql States and ten years in Europe. The European exclusivity period can be reduced to six years if a drug no longer\plain\cf1\f51\fs20\ql meets the criteria for orphan drug designation or if the drug is sufficiently profitable such that market exclusivity is\plain\cf1\f51\fs20\ql no longer justified. Orphan drug exclusivity may be lost if the FDA or EMA determines that the request for\plain\cf1\f51\fs20\ql designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the drug to\plain\cf1\f51\fs20\ql meet the needs of patients with the rare disease or condition.\par\pard\plain\sb528\cf1\f51\fs20\qc 44\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In June 2017, the FDA granted us orphan drug designation for IMO-2125 for the\~treatment of melanoma\plain\cf1\f51\fs20\ql Stages IIb to IV. However, there can be no assurance that we will obtain orphan drug designation or exclusivity for\plain\cf1\f51\fs20\ql any other disease indications for which we develop IMO-2125, or for our other drug candidates. Even if we obtain\plain\cf1\f51\fs20\ql orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition\plain\cf1\f51\fs20\ql because different drugs can be approved for the same condition. Even after an orphan drug is approved, the FDA\plain\cf1\f51\fs20\ql can subsequently approve the same drug for the same condition if the FDA concludes that the later drug is\plain\cf1\f51\fs20\ql clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql On August 3, 2017, Congress passed the FDA Reauthorization Act of 2017, or FDARA. FDARA, among\plain\cf1\f51\fs20\ql other things, codified the FDA\u8217?s pre-existing regulatory interpretation, to require that a drug sponsor\plain\cf1\f51\fs20\ql demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for\plain\cf1\f51\fs20\ql the same rare disease in order to receive orphan drug exclusivity. The new legislation reverses prior precedent\plain\cf1\f51\fs20\ql holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period\plain\cf1\f51\fs20\ql regardless of a showing of clinical superiority. The FDA may further reevaluate the Orphan Drug Act and its\plain\cf1\f51\fs20\ql regulations and policies. We do not know if, when, or how the FDA may change the orphan drug regulations and\plain\cf1\f51\fs20\ql policies in the future, and it is uncertain how any changes might affect our business. Depending on what changes\plain\cf1\f51\fs20\ql the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj A fast track designation by the FDA may not actually lead to a faster development or regulatory review or\plain\cf1\f51\fs20\b\i\qj approval process, and does not increase the likelihood that drug candidates will receive marketing approval.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql We intend to seek fast track designation for some applications of our drug candidates. If a drug is intended\plain\cf1\f51\fs20\ql for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet\plain\cf1\f51\fs20\ql medical needs for this condition, the drug sponsor may apply for FDA fast track designation. The FDA has broad\plain\cf1\f51\fs20\ql discretion whether or not to grant this designation, so even if we believe a particular drug candidate is eligible for\plain\cf1\f51\fs20\ql this designation, we cannot assure you that the FDA would decide to grant it.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In November 2017, the FDA granted us fast track designation for IMO-2125 for the treatment of anti-PD1\plain\cf1\f51\fs20\ql refractory metastatic melanoma in combination with ipilimumab therapy.\~\~However, even with fast track designation,\plain\cf1\f51\fs20\ql we may not experience a faster development process, review or approval compared to conventional FDA\plain\cf1\f51\fs20\ql procedures. The FDA may withdraw fast track designation if it believes that the designation is no longer supported\plain\cf1\f51\fs20\ql by data from our clinical development program.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj A breakthrough therapy designation by the FDA for any application of our drug candidates may not lead to a\plain\cf1\f51\fs20\b\i\qj faster development or regulatory review or approval process, and it does not increase the likelihood that those\plain\cf1\f51\fs20\b\i\qj drug candidates will receive marketing approval.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql We may seek a breakthrough therapy designation for some applications of our drug candidates. A\plain\cf1\f51\fs20\ql breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to\plain\cf1\f51\fs20\ql treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may\plain\cf1\f51\fs20\ql demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as\plain\cf1\f51\fs20\ql substantial treatment effects observed early in clinical development. For drugs and biologics that have been\plain\cf1\f51\fs20\ql designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial\plain\cf1\f51\fs20\ql can help to identify the most efficient path for clinical development while minimizing the number of patients placed\plain\cf1\f51\fs20\ql in ineffective control regimens. Drugs designated as breakthrough therapies by the FDA are also eligible for\plain\cf1\f51\fs20\ql accelerated approval.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if we believe\plain\cf1\f51\fs20\ql an application of one of our drug candidates meets the criteria for designation as a breakthrough therapy, the FDA\plain\cf1\f51\fs20\ql may disagree and instead determine not to make such designation. In any event, the receipt of a breakthrough\plain\cf1\f51\fs20\ql therapy designation for a drug candidate may not result in a faster development process, review or approval\plain\cf1\f51\fs20\ql compared to drugs considered for approval under conventional FDA procedures and does not assure ultimate\plain\cf1\f51\fs20\ql approval by the FDA. In addition, even if one or more of our drug candidates qualify as breakthrough therapies, the\plain\cf1\f51\fs20\ql FDA may later decide that the products no longer meet the conditions for qualification or decide that the time\plain\cf1\f51\fs20\ql period for FDA review or approval will not be shortened.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 45\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\i\qj If we are required by the FDA to obtain approval of a companion diagnostic in connection with and as a\plain\cf1\f51\fs20\b\i\qj condition to approval of a drug candidate, and we do not obtain or we experience delays in obtaining FDA\plain\cf1\f51\fs20\b\i\qj approval of a diagnostic device, we will not be able to commercialize the drug candidate and our ability to\plain\cf1\f51\fs20\b\i\qj generate revenue will be materially impaired.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql According to FDA guidance, if the FDA determines that a companion diagnostic device is essential to the\plain\cf1\f51\fs20\ql safe and effective use of a novel therapeutic product or indication, the FDA generally will not approve the\plain\cf1\f51\fs20\ql therapeutic product or new therapeutic product indication if the companion diagnostic is not also approved or\plain\cf1\f51\fs20\ql cleared for that indication. Under the Federal Food, Drug, and Cosmetic Act, companion diagnostics are regulated\plain\cf1\f51\fs20\ql as medical devices and the FDA has generally required companion diagnostics intended to select the patients who\plain\cf1\f51\fs20\ql will respond to cancer treatment to obtain Premarket Approval, or a PMA. The PMA process, including the\plain\cf1\f51\fs20\ql gathering of clinical and preclinical data and the submission to and review by the FDA, involves a rigorous\plain\cf1\f51\fs20\ql premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the\plain\cf1\f51\fs20\ql device's safety and effectiveness and information about the device and its components regarding, among other\plain\cf1\f51\fs20\ql things, device design, manufacturing and labeling. PMA approval is not guaranteed and may take considerable time,\plain\cf1\f51\fs20\ql and the FDA may ultimately respond to a PMA submission with a not approvable determination based on\plain\cf1\f51\fs20\ql deficiencies in the application and require additional clinical trial or other data that may be expensive and\plain\cf1\f51\fs20\ql time-consuming to generate and that can substantially delay approval.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We do not have experience or capabilities in developing or commercializing diagnostics and plan to rely on\plain\cf1\f51\fs20\ql third parties or collaborators to perform these functions. Companion diagnostics are subject to regulation by the\plain\cf1\f51\fs20\ql FDA and similar regulatory authorities outside the United States as medical devices and require separate regulatory\plain\cf1\f51\fs20\ql approval prior to commercialization.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If we, or any third parties that we engage to assist us or any of our collaborators, are unable to successfully\plain\cf1\f51\fs20\ql develop companion diagnostics for our TLR antagonist drug candidates that require a companion diagnostic, or\plain\sa132\cf1\f51\fs20\ql experience delays in doing so:
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the development of such TLR antagonist drug candidates may be adversely affected if we are unable to\plain\intbl\sa132\cf1\f51\fs20\qj appropriately select patients for enrollment in our clinical trials;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj such TLR antagonist drug candidates may not receive marketing approval if their safe and effective use\plain\intbl\sa132\cf1\f51\fs20\qj depends on a companion diagnostic; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh878
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj we may not realize the full commercial potential of any TLR antagonist drug candidate that receives\plain\intbl\cf1\f51\fs20\qj marketing approval if, among other reasons, we are unable to appropriately identify patients with the\plain\intbl\sa132\cf1\f51\fs20\qj specific oncogenic mutation targeted by such TLR antagonist drug candidate.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh878\row}}}\pard\plain\fi594\cf1\f51\fs20\ql If any of these events were to occur, our business would be harmed, possibly materially.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We have only limited experience in regulatory affairs and our drug candidates are based on new technologies;\plain\cf1\f51\fs20\b\i\qj these factors may affect our ability or the time we require to obtain necessary regulatory approvals.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have only limited experience in filing the applications necessary to obtain regulatory approvals.\plain\cf1\f51\fs20\ql Moreover, the products that result from our research and development programs will likely be based on new\plain\cf1\f51\fs20\ql technologies and new therapeutic approaches that have not been extensively tested in humans. The regulatory\plain\cf1\f51\fs20\ql requirements governing these types of products may be more rigorous than for conventional drugs. As a result, we\plain\cf1\f51\fs20\ql may experience a longer regulatory process in connection with obtaining regulatory approvals of any product that\plain\cf1\f51\fs20\ql we develop.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Our relationships with healthcare providers and physicians and third-party payors will be subject to applicable\plain\cf1\f51\fs20\b\i\qj anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal\plain\cf1\f51\fs20\b\i\qj sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql Healthcare providers, physicians and third party payors will play a primary role in the recommendation and\plain\cf1\f51\fs20\ql prescription of any drugs for which we obtain marketing approval. Our future arrangements with third party payors,\plain\cf1\f51\fs20\ql healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare\par\pard\plain\sb528\cf1\f51\fs20\qc 46\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\sb264\cf1\f51\fs20\ql laws and regulations that may constrain the business or financial arrangements and relationships through which we\plain\cf1\f51\fs20\ql market, sell and distribute any drugs for which we obtain marketing approval. These include the following:\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~Anti-Kickback Statute\u8212?the federal healthcare anti-kickback statute prohibits, among other\plain\li990\cf1\f51\fs20\ql things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration,\plain\li990\cf1\f51\fs20\ql directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an\plain\li990\cf1\f51\fs20\ql individual for, or the purchase, order or recommendation or arranging of, any good or service, for which\plain\li990\cf1\f51\fs20\ql payment may be made under a federal healthcare program such as Medicare and Medicaid;\plain\li990\cf1\f51\fs2\ql \~\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?False Claims Act\u8212?the federal False Claims Act imposes criminal and civil penalties, including\plain\li990\cf1\f51\fs20\ql through civil whistleblower or qui tam actions, against individuals or entities for, among other things,\plain\li990\cf1\f51\fs20\ql knowingly presenting, or causing to be presented false or fraudulent claims for payment by a federal\plain\li990\cf1\f51\fs20\ql healthcare program or making a false statement or record material to payment of a false claim or\plain\li990\cf1\f51\fs20\ql avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential\plain\li990\cf1\f51\fs20\ql liability including mandatory treble damages and significant per-claim penalties, currently set at $5,500\plain\li990\cf1\f51\fs20\ql to $11,000 per false claim;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?HIPAA\u8212?the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA,\plain\li990\cf1\f51\fs20\ql imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or\plain\li990\cf1\f51\fs20\ql making false statements relating to healthcare matters, and, as amended by the Health Information\plain\li990\cf1\f51\fs20\ql Technology for Economic and Clinical Health Act and its implementing regulations, also imposes\plain\li990\cf1\f51\fs20\ql obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining\plain\li990\cf1\f51\fs20\ql the privacy, security and transmission of individually identifiable health information;\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226? \~Transparency Requirements\u8212?federal laws require applicable manufacturers of covered drugs to\plain\li990\cf1\f51\fs20\ql report payments and other transfers of value to physicians and teaching hospitals; and\par\pard\plain\li990\sb132\fi-396\cf1\f51\fs20\ql \u8226?Analogous State and Foreign Laws\u8212?analogous state and foreign fraud and abuse laws and\plain\li990\cf1\f51\fs20\ql regulations, such as state anti-kickback and false claims laws, can apply to sales or marketing\plain\li990\cf1\f51\fs20\ql arrangements and claims involving healthcare items or services and are generally broad and are enforced\plain\li990\cf1\f51\fs20\ql by many different federal and state agencies as well as through private actions.\par\pard\plain\sb264\fi594\cf1\f51\fs20\ql Some state laws require pharmaceutical companies to comply with the pharmaceutical industry\u8217?s\plain\cf1\f51\fs20\ql voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and\plain\cf1\f51\fs20\ql require drug manufacturers to report information related to payments and other transfers of value to physicians and\plain\cf1\f51\fs20\ql other healthcare providers or marketing expenditures. State and foreign laws also govern the privacy and security of\plain\cf1\f51\fs20\ql health information in some circumstances, many of which differ from each other in significant ways and often are\plain\cf1\f51\fs20\ql not pre-empted by HIPAA, thus complicating compliance efforts.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare\plain\cf1\f51\fs20\ql laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that our\plain\cf1\f51\fs20\ql business practices may not comply with current or future statutes, regulations or case law involving applicable fraud\plain\cf1\f51\fs20\ql and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these\plain\cf1\f51\fs20\ql laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal\plain\cf1\f51\fs20\ql and administrative penalties, damages, fines, imprisonment, exclusion of products from government funded\plain\cf1\f51\fs20\ql healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations. If any\plain\cf1\f51\fs20\ql of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in\plain\cf1\f51\fs20\ql compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including\plain\cf1\f51\fs20\ql exclusions from government funded healthcare programs.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj Current and future legislation may increase the difficulty and cost for us and any collaborators to obtain\plain\cf1\f51\fs20\b\i\qj marketing approval of our drug candidates and may affect the prices we, or they, may obtain.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory\plain\cf1\f51\fs20\ql changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay\plain\cf1\f51\fs20\ql marketing approval of our drug candidates, restrict or regulate post-approval activities and affect our ability, or the\plain\cf1\f51\fs20\ql ability of any collaborators, to profitably sell any products for which we, or they, obtain marketing approval. We\plain\cf1\f51\fs20\ql expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result\plain\cf1\f51\fs20\ql in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators,\plain\cf1\f51\fs20\ql may receive for any approved products.\par\pard\plain\sb528\cf1\f51\fs20\qc 47\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql For example, in March 2010, President Obama signed into law the Patient Protection and Affordable Care\plain\cf1\f51\fs20\ql Act, as amended by the Health Care and Education Reconciliation Act, or collectively the PPACA. Among the\plain\cf1\f51\fs20\ql provisions of the PPACA of potential importance to our business and our drug candidates are the following:\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?an annual, non-deductible fee on any entity that manufactures or imports specified branded\plain\li1078\cf1\f51\fs20\ql prescription drugs and biologic agents;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug\plain\li1078\cf1\f51\fs20\ql Rebate Program;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?expansion of healthcare fraud and abuse laws, including the civil False Claims Act and the federal\plain\li1078\cf1\f51\fs20\ql Anti-Kickback Statute, new government investigative powers and enhanced penalties for\plain\li1078\cf1\f51\fs20\ql noncompliance;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer\plain\li1078\cf1\f51\fs20\ql 50% point-of-sale discounts off negotiated prices;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?extension of manufacturers\u8217? Medicaid rebate liability;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?expansion of eligibility criteria for Medicaid programs;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing\plain\li1078\cf1\f51\fs20\ql program;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?new requirements to report certain financial arrangements with physicians and teaching hospitals;\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?a new requirement to annually report drug samples that manufacturers and distributors provide to\plain\li1078\cf1\f51\fs20\ql physicians; and\par\pard\plain\li1078\sb132\fi-484\cf1\f51\fs20\ql \u8226?a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct\plain\li1078\cf1\f51\fs20\ql comparative clinical effectiveness research, along with funding for such research.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, other legislative changes have been proposed and adopted since the PPACA was enacted. These\plain\cf1\f51\fs20\ql changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions to\plain\cf1\f51\fs20\ql Medicare payments to providers of up to 2% per fiscal year that started in 2013 and, due to subsequent legislative\plain\cf1\f51\fs20\ql amendments to the statute, will stay in effect through 2025 unless additional congressional action is taken, and the\plain\cf1\f51\fs20\ql American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several types of\plain\cf1\f51\fs20\ql providers and increased the statute of limitations period for the government to recover overpayments to providers\plain\cf1\f51\fs20\ql from three to five years. These new laws may result in additional reductions in Medicare and other healthcare\plain\cf1\f51\fs20\ql funding and otherwise affect the prices we may obtain for any of our drug candidates for which we may obtain\plain\cf1\f51\fs20\ql regulatory approval or the frequency with which any such drug candidate is prescribed or used. Further, there have\plain\cf1\f51\fs20\ql been several recent U.S. congressional inquiries and proposed state and federal legislation designed to, among other\plain\cf1\f51\fs20\ql things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient\plain\cf1\f51\fs20\ql programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies\plain\cf1\f51\fs20\ql for drug products.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We expect that these healthcare reforms, as well as other healthcare reform measures that may be adopted in\plain\cf1\f51\fs20\ql the future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage\plain\cf1\f51\fs20\ql criteria, new payment methodologies and additional downward pressure on the price that we receive for any\plain\cf1\f51\fs20\ql approved product and/or the level of reimbursement physicians receive for administering any approved product we\plain\cf1\f51\fs20\ql might bring to market. Reductions in reimbursement levels may negatively impact the prices we receive or the\plain\cf1\f51\fs20\ql frequency with which our products are prescribed or administered.\~\~Any reduction in reimbursement from Medicare\plain\cf1\f51\fs20\ql or other government programs may result in a similar reduction in payments from private payors.\~\~Since enactment\plain\cf1\f51\fs20\ql of the PPACA, there have been numerous legal challenges and Congressional actions to repeal and replace\plain\cf1\f51\fs20\ql provisions of the law.\~\~In May 2017, the House of Representatives passed legislation known as the American Health\plain\cf1\f51\fs20\ql Care Act of 2017.\~\~Thereafter, the Senate Republicans introduced and then updated a bill to replace the PPACA\plain\cf1\f51\fs20\ql known as the Better Care Reconciliation Act of 2017. The Senate Republicans also introduced legislation to repeal\plain\cf1\f51\fs20\ql the PPACA without companion legislation to replace it, and a \u8220?skinny\u8221? version of the Better Care\plain\cf1\f51\fs20\ql Reconciliation Act of 2017.\~\~In addition, the Senate considered proposed healthcare reform legislation known as the\plain\cf1\f51\fs20\ql Graham-Cassidy bill.\~\~None of these measures was passed by the Senate.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 48\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\ql The Trump Administration has also taken executive actions to undermine or delay implementation of the\plain\cf1\f51\fs20\ql PPACA.\~\~In January 2017, President Trump signed an Executive Order directing federal agencies with authorities\plain\cf1\f51\fs20\ql and responsibilities under the PPACA to waive, defer, grant exemptions from, or delay the implementation of any\plain\cf1\f51\fs20\ql provision of the PPACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers,\plain\cf1\f51\fs20\ql health insurers, or manufacturers of pharmaceuticals or medical devices.\~\~In October 2017, the President signed a\plain\cf1\f51\fs20\ql second Executive Order allowing for the use of association health plans and short-term health insurance, which may\plain\cf1\f51\fs20\ql provide fewer health benefits than the plans sold through the PPACA exchanges.\~\~At the same time, the\plain\cf1\f51\fs20\ql Administration announced that it will discontinue the payment of cost-sharing reduction, or CSR, payments to\plain\cf1\f51\fs20\ql insurance companies until Congress approves the appropriation of funds for such CSR payments. The loss of the\plain\cf1\f51\fs20\ql CSR payments is expected to increase premiums on certain policies issued by qualified health plans under the\plain\cf1\f51\fs20\ql PPACA.\~\~A bipartisan bill to appropriate funds for CSR payments was introduced in the Senate, but the future of\plain\cf1\f51\fs20\ql that bill is uncertain.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql More recently, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by the President on\plain\cf1\f51\fs20\ql December 22, 2017, Congress repealed the \u8220?individual mandate.\u8221?\~\~The repeal of this provision, which\plain\cf1\f51\fs20\ql requires most Americans to carry a minimal level of health insurance, will become effective in 2019.\~\~According to\plain\cf1\f51\fs20\ql the Congressional Budget Office, the repeal of the individual mandate will cause 13 million fewer Americans to be\plain\cf1\f51\fs20\ql insured in 2027 and premiums in insurance markets may rise.\~\~Further, each chamber of the Congress has put forth\plain\cf1\f51\fs20\ql multiple bills designed to repeal or repeal and replace portions of the PPACA. Although none of these measures has\plain\cf1\f51\fs20\ql been enacted by Congress to date, Congress may consider other legislation to repeal and replace elements of the\plain\cf1\f51\fs20\ql PPACA. Congress will likely consider other legislation to replace elements of the PPACA, during the next\plain\cf1\f51\fs20\ql Congressional session.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We will continue to evaluate the effect that the PPACA and its possible repeal and replacement could have\plain\cf1\f51\fs20\ql on our business.\~\~It is possible that repeal and replacement initiatives, if enacted into law, could ultimately result in\plain\cf1\f51\fs20\ql fewer individuals having health insurance coverage or in individuals having insurance coverage with less generous\plain\cf1\f51\fs20\ql benefits.\~\~While the timing and scope of any potential future legislation to repeal and replace PPACA provisions is\plain\cf1\f51\fs20\ql highly uncertain in many respects, it is also possible that some of the PPACA provisions that generally are not\plain\cf1\f51\fs20\ql favorable for the research-based pharmaceutical industry could also be repealed along with PPACA coverage\plain\cf1\f51\fs20\ql expansion provisions Accordingly, such reforms, if enacted, could have an adverse effect on anticipated revenue\plain\cf1\f51\fs20\ql from drug candidates that we may successfully develop and for which we may obtain marketing approval and may\plain\cf1\f51\fs20\ql affect our overall financial condition and ability to develop commercialize drug candidates.\~\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The costs of prescription pharmaceuticals in the United States has also been the subject of considerable\plain\cf1\f51\fs20\ql discussion in the United States, and members of Congress and the Administration have stated that they will address\plain\cf1\f51\fs20\ql such costs through new legislative and administrative measures.\~\~The pricing of prescription pharmaceuticals is also\plain\cf1\f51\fs20\ql subject to governmental control outside the United States.\~\~In these countries, pricing negotiations with governmental\plain\cf1\f51\fs20\ql authorities can take considerable time after the receipt of marketing approval for a product. To obtain\plain\cf1\f51\fs20\ql reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares\plain\cf1\f51\fs20\ql the cost effectiveness of our drug candidates to other available therapies. If reimbursement of our products is\plain\cf1\f51\fs20\ql unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to generate\plain\cf1\f51\fs20\ql revenues and become profitable could be impaired.\~\~In the European Union, similar political, economic and\plain\cf1\f51\fs20\ql regulatory developments may affect our ability to profitably commercialize our products. In addition to continuing\plain\cf1\f51\fs20\ql pressure on prices and cost containment measures, legislative developments at the European Union or member state\plain\cf1\f51\fs20\ql level may result in significant additional requirements or obstacles that may increase our operating costs.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Moreover, legislative and regulatory proposals have also been made to expand post-approval requirements\plain\cf1\f51\fs20\ql and restrict sales and promotional activities for pharmaceutical drugs. We cannot be sure whether additional\plain\cf1\f51\fs20\ql legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or\plain\cf1\f51\fs20\ql what the impact of such changes on the marketing approvals of our drug candidates, if any, may be. In addition,\plain\cf1\f51\fs20\ql increased scrutiny by Congress of the FDA\u8217?s approval process may significantly delay or prevent marketing\plain\cf1\f51\fs20\ql approval, as well as subject us and any future collaborators to more stringent drug labeling and post-marketing\plain\cf1\f51\fs20\ql testing and other requirements.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 49\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\i\qj Laws and regulations governing any international operations we may have in the future may preclude us from\plain\cf1\f51\fs20\b\i\qj developing, manufacturing and selling certain drug candidates outside of the United States and require us to\plain\cf1\f51\fs20\b\i\qj develop and implement costly compliance programs.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are subject to numerous laws and regulations in each jurisdiction outside the United States in which we\plain\cf1\f51\fs20\ql operate. The creation, implementation and maintenance of international business practices compliance programs is\plain\cf1\f51\fs20\ql costly and such programs are difficult to enforce, particularly where reliance on third parties is required.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The FCPA prohibits any U.S. individual or business from paying, offering, authorizing payment or offering of\plain\cf1\f51\fs20\ql anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of\plain\cf1\f51\fs20\ql influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or\plain\cf1\f51\fs20\ql retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply\plain\cf1\f51\fs20\ql with certain accounting provisions requiring the company to maintain books and records that accurately and fairly\plain\cf1\f51\fs20\ql reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an\plain\cf1\f51\fs20\ql adequate system of internal accounting controls for international operations. The anti-bribery provisions of the\plain\cf1\f51\fs20\ql FCPA are enforced primarily by the DOJ. The Securities and Exchange Commission, or SEC, is involved with\plain\cf1\f51\fs20\ql enforcement of the books and records provisions of the FCPA.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a\plain\cf1\f51\fs20\ql recognized problem. In addition, the FCPA presents particular challenges in the pharmaceutical industry, because, in\plain\cf1\f51\fs20\ql many countries, hospitals are operated by the government, and doctors and other hospital employees are considered\plain\cf1\f51\fs20\ql foreign officials. Certain payments to hospitals in connection with clinical trials and other work have been deemed\plain\cf1\f51\fs20\ql to be improper payments to government officials and have led to FCPA enforcement actions.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Various laws, regulations and executive orders also restrict the use and dissemination outside of the United\plain\cf1\f51\fs20\ql States, or the sharing with certain non-U.S. nationals, of information classified for national security purposes, as\plain\cf1\f51\fs20\ql well as certain products and technical data relating to those products. Our expansion outside of the United States,\plain\cf1\f51\fs20\ql has required, and will continue to require, us to dedicate additional resources to comply with these laws, and these\plain\cf1\f51\fs20\ql laws may preclude us from developing, manufacturing, or selling certain drugs and drug candidates outside of the\plain\cf1\f51\fs20\ql United States, which could limit our growth potential and increase our development costs. The failure to comply\plain\cf1\f51\fs20\ql with laws governing international business practices may result in substantial penalties, including suspension or\plain\cf1\f51\fs20\ql debarment from government contracting. Violation of the FCPA can result in significant civil and criminal penalties.\plain\cf1\f51\fs20\ql Indictment alone under the FCPA can lead to suspension of the right to do business with the U.S. government until\plain\cf1\f51\fs20\ql the pending claims are resolved. Conviction of a violation of the FCPA can result in long-term disqualification as a\plain\cf1\f51\fs20\ql government contractor. The termination of a government contract or relationship as a result of our failure to satisfy\plain\cf1\f51\fs20\ql any of our obligations under laws governing international business practices would have a negative impact on our\plain\cf1\f51\fs20\ql operations and harm our reputation and ability to procure government contracts. The SEC also may suspend or bar\plain\cf1\f51\fs20\ql issuers from trading securities on U.S. exchanges for violations of the FCPA\u8217?s accounting provisions.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Governments outside of the United States tend to impose strict price controls, which may adversely affect our\plain\cf1\f51\fs20\b\i\qj revenues from the sales of drugs, if any.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In some countries, particularly the countries of the European Union, the pricing of prescription\plain\cf1\f51\fs20\ql pharmaceuticals is subject to governmental control. In these countries, pricing negotiations with governmental\plain\cf1\f51\fs20\ql authorities can take considerable time after the receipt of marketing approval for a drug. To obtain reimbursement\plain\cf1\f51\fs20\ql or pricing approval in some countries, we, or our future collaborators, may be required to conduct a clinical trial\plain\cf1\f51\fs20\ql that compares the cost-effectiveness of our drug to other available therapies. If reimbursement of our drugs is\plain\cf1\f51\fs20\ql unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be\plain\cf1\f51\fs20\ql materially harmed.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines\plain\cf1\f51\fs20\b\i\qj or penalties or incur costs that could have a material adverse effect on our business.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are subject to numerous environmental, health and safety laws and regulations, including those governing\plain\cf1\f51\fs20\ql laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our\plain\cf1\f51\fs20\ql operations involve the use of hazardous and flammable materials, including chemicals and biological and radioactive\plain\cf1\f51\fs20\ql materials. Our operations also produce hazardous waste products. We generally contract with third parties for the\plain\cf1\f51\fs20\ql disposal of these materials and wastes. We cannot eliminate the risk of contamination or\par\pard\plain\sb528\cf1\f51\fs20\qc 50\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials,\plain\cf1\f51\fs20\ql we could be held liable for any resulting damages, and any liability could exceed our resources. We also could\plain\cf1\f51\fs20\ql incur significant costs associated with civil or criminal fines and penalties.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Although we maintain workers\u8217? compensation insurance to cover us for costs and expenses we may\plain\cf1\f51\fs20\ql incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide\plain\cf1\f51\fs20\ql adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort\plain\cf1\f51\fs20\ql claims that may be asserted against us in connection with our storage or disposal of biological, hazardous or\plain\cf1\f51\fs20\ql radioactive materials.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, we may incur substantial costs in order to comply with current or future environmental, health\plain\cf1\f51\fs20\ql and safety laws and regulations. These current or future laws and regulations may impair our research, development\plain\cf1\f51\fs20\ql or commercialization efforts. Failure to comply with these laws and regulations also may result in substantial fines,\plain\cf1\f51\fs20\ql penalties or other sanctions.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Our employees may engage in misconduct or other improper activities, including non-compliance with regulatory\plain\cf1\f51\fs20\b\i\qj standards and requirements, which could cause significant liability for us and harm our reputation.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are exposed to the risk of employee fraud or other misconduct, including intentional failures to comply\plain\cf1\f51\fs20\ql with FDA regulations or similar regulations of comparable foreign regulatory authorities, provide accurate\plain\cf1\f51\fs20\ql information to the FDA or comparable foreign regulatory authorities, comply with manufacturing standards we have\plain\cf1\f51\fs20\ql established, comply with federal and state healthcare fraud and abuse laws and regulations and similar laws and\plain\cf1\f51\fs20\ql regulations established and enforced by comparable foreign regulatory authorities, report financial information or\plain\cf1\f51\fs20\ql data accurately or disclose unauthorized activities to us. Employee misconduct could also involve the improper use\plain\cf1\f51\fs20\ql of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm\plain\cf1\f51\fs20\ql to our reputation. It is not always possible to identify and deter employee misconduct, and the precautions we take\plain\cf1\f51\fs20\ql to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in\plain\cf1\f51\fs20\ql protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in\plain\cf1\f51\fs20\ql compliance with such laws, standards or regulations. If any such actions are instituted against us, and we are not\plain\cf1\f51\fs20\ql successful in defending ourselves or asserting our rights, those actions could have a significant impact on our\plain\sa132\cf1\f51\fs20\ql business and results of operations, including the imposition of significant fines or other sanctions.\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\qc Risks{\*\bkmkstart _cp_text_1_321_12112272}{\*\bkmkend _cp_text_1_321_12112272}\plain\cf1\f51\fs20\b\qc Relating to Collaborators\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\i\qj Our existing collaborations and any collaborations we enter into in the future may not be successful.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Historically, an important element of our business strategy has included entering into collaborative alliances\plain\cf1\f51\fs20\ql with corporate collaborators, primarily large pharmaceutical companies, for the development, commercialization,\plain\cf1\f51\fs20\ql marketing, and distribution of some of our drug candidates. In December 2006, we entered into an exclusive license\plain\cf1\f51\fs20\ql and research collaboration with Merck & Co. to research, develop, and commercialize vaccine products containing\plain\cf1\f51\fs20\ql our TLR7, TLR8 and TLR9 agonists in the fields of cancer, infectious diseases, and Alzheimer's disease. In\plain\cf1\f51\fs20\ql November 2015, we entered into a collaboration and license agreement with GSK for the development of our\plain\cf1\f51\fs20\ql nucleic acid chemistry technology for certain renal indications and in November 2016, we entered into a license\plain\cf1\f51\fs20\ql agreement with Vivelix granting them exclusive rights for the development of IMO-9200 for non-malignant\plain\cf1\f51\fs20\ql indication of the GI Field.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Any collaboration we enter into may not be successful. The success of our collaborative alliances, if any, will\plain\cf1\f51\fs20\ql depend heavily on the efforts and activities of our collaborators. Our existing collaborations and any potential future\plain\cf1\f51\fs20\ql collaborations have risks, including the following:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may control the development of the companion diagnostic to be developed for use in\plain\intbl\sa132\cf1\f51\fs20\ql conjunction with our drug candidates including the timing of development;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may control the public release of information regarding the developments, and we may\plain\intbl\sa132\cf1\f51\fs20\ql not be able to make announcements or data presentations on a schedule favorable to us;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh630\row}}}\pard\plain\sb528\cf1\f51\fs20\qc 51\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql disputes may arise in the future with respect to the ownership of or right to use technology and\plain\intbl\sa132\cf1\f51\fs20\ql intellectual property developed with our collaborators;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql disagreements with our collaborators could delay or terminate the research, development or\plain\intbl\sa132\cf1\f51\fs20\ql commercialization of products, or result in litigation or arbitration;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may terminate their collaborations with us, which could make it difficult for us to\plain\intbl\cf1\f51\fs20\ql attract new collaborators or adversely affect the perception of us in the business or financial\plain\intbl\sa132\cf1\f51\fs20\ql communities;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaboration agreements are likely to be for fixed terms and subject to termination by our\plain\intbl\sa132\cf1\f51\fs20\ql collaborators in the event of a material breach or lack of scientific progress by us;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1148
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may have the first right to maintain or defend our intellectual property rights and,\plain\intbl\cf1\f51\fs20\ql although we would likely have the right to assume the maintenance and defense of our intellectual\plain\intbl\cf1\f51\fs20\ql property rights if our collaborators do not, our ability to do so may be compromised by our collaborators'\plain\intbl\sa132\cf1\f51\fs20\ql acts or omissions;\cell{
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may challenge our intellectual property rights or utilize our intellectual\plain\intbl\cf1\f51\fs20\ql property rights in such a way as to invite litigation that could jeopardize or invalidate our\plain\intbl\sa132\cf1\f51\fs20\ql intellectual property rights or expose us to potential liability;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may not comply with all applicable regulatory requirements, or may fail to report safety\plain\intbl\sa132\cf1\f51\fs20\ql data in accordance with all applicable regulatory requirements;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may change the focus of their development and commercialization efforts.\plain\intbl\cf1\f51\fs20\ql Pharmaceutical and biotechnology companies historically have re-evaluated their priorities following\plain\intbl\cf1\f51\fs20\ql mergers and consolidations, which have been common in recent years in these industries. The ability of\plain\intbl\cf1\f51\fs20\ql our drug candidates to reach their potential could be limited if our collaborators decrease or fail to\plain\intbl\sa132\cf1\f51\fs20\ql increase spending relating to such drug candidates;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may under fund or not commit sufficient resources to the testing, marketing,\plain\intbl\sa132\cf1\f51\fs20\ql distribution or development of our drug candidates; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh765
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our collaborators may develop alternative products either on their own or in collaboration with\plain\intbl\cf1\f51\fs20\ql others, or encounter conflicts of interest or changes in business strategy or other business\plain\intbl\cf1\f51\fs20\ql issues, which could adversely affect their willingness or ability to fulfill their obligations to us.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh765\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Given these risks, it is possible that any collaborative alliance into which we enter may not be successful.\plain\cf1\f51\fs20\ql Collaborations with pharmaceutical companies and other third parties often are terminated or allowed to expire by\plain\cf1\f51\fs20\ql the other party. The termination or expiration of our current collaboration agreements or any other collaboration\plain\cf1\f51\fs20\ql agreement that we enter into in the future may adversely affect us financially and could harm our business\plain\cf1\f51\fs20\ql reputation. \~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj If we are unable to establish additional collaborative alliances, our business may be materially harmed.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Collaborators provide the necessary resources and drug development experience to advance our compounds in\plain\cf1\f51\fs20\ql their programs. We have entered into and expect to continue to seek to enter into collaborative alliances with\plain\cf1\f51\fs20\ql pharmaceutical companies to advance our TLR agonist and antagonist candidates and with respect to additional\plain\cf1\f51\fs20\ql applications of our nucleic acid chemistry technology research program. Upfront payments and milestone payments\plain\cf1\f51\fs20\ql received from collaborations help to provide us with the financial resources for our internal research and\plain\cf1\f51\fs20\ql development programs. Our internal programs are focused on developing TLR-targeted drug candidates for the\plain\cf1\f51\fs20\ql potential treatment of certain rare diseases and in our immuno-oncology program and on nucleic acid chemistry\plain\cf1\f51\fs20\ql drug candidates. We believe that additional resources will be required to advance compounds in all of these areas. If\plain\cf1\f51\fs20\ql we do not reach agreements with additional collaborators in the future, we may not be able to obtain the expertise\plain\cf1\f51\fs20\ql and resources necessary to achieve our business objectives, our ability to advance our compounds will be\plain\cf1\f51\fs20\ql jeopardized and we may fail to meet our business objectives.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We may have difficulty establishing additional collaborative alliances, particularly with respect to our\plain\cf1\f51\fs20\ql TLR-targeted drug candidates and technology and our nucleic acid chemistry technology. For example, potential\par\pard\plain\sb528\cf1\f51\fs20\qc 52\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql collaborators may note that our prior TLR collaborations with Novartis and with Merck KGaA have been\plain\cf1\f51\fs20\ql terminated. Potential collaborators may also be reluctant to establish collaborations with respect to IMO-2125 or\plain\cf1\f51\fs20\ql IMO-8400, given our prior setbacks with respect to these drug candidates. We also face, and expect to continue to\plain\cf1\f51\fs20\ql face, significant competition in seeking appropriate collaborators.\~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Even if a potential partner were willing to enter into a collaborative alliance with respect to our\plain\cf1\f51\fs20\ql TLR-targeted compounds or technology or our nucleic acid chemistry technology, the terms of such a collaborative\plain\cf1\f51\fs20\ql alliance may not be on terms that are favorable to us. Moreover, collaborations are complex and time consuming to\plain\cf1\f51\fs20\ql negotiate, document, and implement. We may not be successful in our efforts to establish and implement\plain\sa132\cf1\f51\fs20\ql collaborations on a timely basis.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\qc Risks{\*\bkmkstart _cp_text_1_323_12112272}{\*\bkmkend _cp_text_1_323_12112272}\plain\cf1\f51\fs20\b\qc Relating to Intellectual Property\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\i\qj If we are unable to obtain and maintain patent protection for our discoveries, the value of our technology and\plain\cf1\f51\fs20\b\i\qj products will be adversely affected.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our patent positions, and those of other drug discovery companies, are generally uncertain and involve\plain\cf1\f51\fs20\ql complex legal, scientific, and factual questions. Our ability to develop and commercialize drugs depends in\plain\sa132\cf1\f51\fs20\ql significant part on our ability to:
\par\pard\plain
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh382\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh382\row}}}
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj operate without infringing upon the proprietary rights of others;{\*\bkmkstart _cp_text_1_326_12112272}{\*\bkmkend _cp_text_1_326_12112272}\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh382\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh382
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj prevent others from infringing on our proprietary rights; and{\*\bkmkstart _cp_text_1_327_12112272}{\*\bkmkend _cp_text_1_327_12112272}\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh382\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj protect our trade secrets.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql We do not know whether any of our currently pending patent applications or those patent applications that\plain\cf1\f51\fs20\ql we license will result in the issuance of any patents. Our issued patents and those that may be issued in the future,\plain\cf1\f51\fs20\ql or those licensed to us, may be challenged, invalidated, held unenforceable, narrowed in the course of a\plain\cf1\f51\fs20\ql post-issuance proceeding or circumvented, and the rights granted thereunder may not provide us proprietary\plain\cf1\f51\fs20\ql protection or competitive advantages against competitors with similar technology. Moreover, intellectual property\plain\cf1\f51\fs20\ql laws may change and negatively impact our ability to obtain issued patents covering our technologies or to enforce\plain\cf1\f51\fs20\ql any patents that issue. Because of the extensive time required for development, testing, and regulatory review of a\plain\cf1\f51\fs20\ql potential product, it is possible that, before any of our products can be commercialized, any related patent may\plain\cf1\f51\fs20\ql expire or remain in force for only a short period following commercialization, thus reducing any advantage provided\plain\cf1\f51\fs20\ql by the patent.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Because patent applications in the United States and many foreign jurisdictions are typically not published\plain\cf1\f51\fs20\ql until 18 months after filing, or in some cases not at all, and because publications of discoveries in the scientific\plain\cf1\f51\fs20\ql literature often lag behind actual discoveries, neither we nor our licensors can be certain that we or they were the\plain\cf1\f51\fs20\ql first to make the inventions claimed in issued patents or pending patent applications, or that we or they were the\plain\cf1\f51\fs20\ql first to file for protection of the inventions set forth in these patent applications.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of February 15, 2018, we owned about 49 U.S. patents and patent applications and about 136 patents and\plain\cf1\f51\fs20\ql patent applications throughout the rest of the world for our TLR-targeted immune modulation technologies. These\plain\cf1\f51\fs20\ql patents and patent applications include claims covering the chemical compositions of matter and methods of use of\plain\cf1\f51\fs20\ql our IMO compounds, such as IMO-8400, IMO-9200 and IMO-2125, as well as other compounds. These patents\plain\cf1\f51\fs20\ql expire at various dates ranging from 2023 to 2037. With respect to IMO-8400, we have five issued U.S. patents\plain\cf1\f51\fs20\ql that cover the chemical composition of matter of IMO-8400 and certain methods of its use that provide exclusivity\plain\cf1\f51\fs20\ql for IMO-8400 until at least 2031. With respect to IMO-9200, we have six issued U.S. patents and two U.S. patent\plain\cf1\f51\fs20\ql applications that cover the chemical composition for IMO-9200 and methods of its use that provide exclusivity for\plain\cf1\f51\fs20\ql IMO-9200 until at least 2034. With respect to IMO-2125, we have an issued U.S. patent that covers the chemical\plain\cf1\f51\fs20\ql composition of matter of IMO-2125 and methods of its use that will expire in 2025. We have pending applications\plain\cf1\f51\fs20\ql in the U.S. and outside of the U.S. that cover methods of treatment or use with IMO-2125 with expiration dates of\plain\cf1\f51\fs20\ql 2035 and 2037.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 53\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\ql As of February 15, 2018, we owned three issued U.S. patents, 25 issued foreign patents, five pending U.S.\plain\cf1\f51\fs20\ql patent applications and 12 foreign patent applications (including pending applications under the Patent Cooperation\plain\cf1\f51\fs20\ql Treaty, or PCT) related to our nucleic acid chemistry compounds and methods of their use. The issued patents\plain\cf1\f51\fs20\ql covering our nucleic acid chemistry technologies have{\*\bkmkstart _cp_text_1_284_12112272}{\*\bkmkend _cp_text_1_284_12112272}\plain\cf1\f51\fs20\ql an earliest statutory expiration date in 2030. One patent\plain\cf1\f51\fs20\ql family relating to targets for our nucleic acid chemistry compounds is in-licensed.\~\~\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Third parties may own or control patents or patent applications and require us to seek licenses, which could\plain\cf1\f51\fs20\b\i\qj increase our development and commercialization costs, or prevent us from developing or marketing products.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Although we have many issued patents and pending patent applications in the United States and other\plain\cf1\f51\fs20\ql countries, we may not have rights under certain third-party patents or patent applications related to our compounds\plain\cf1\f51\fs20\ql under development. Third parties may own or control these patents and patent applications in the United States and\plain\cf1\f51\fs20\ql abroad. In particular, we are aware of certain third-party U.S. patents that contain claims related to\plain\cf1\f51\fs20\ql immunostimulatory polynucleotides and their use to stimulate an immune response, as well as to antisense\plain\cf1\f51\fs20\ql technology. Although we do not believe any of our TLR or antisense compounds under development infringe any\plain\cf1\f51\fs20\ql valid claim of these patents, we cannot be assured that the holder of such patents would not seek to assert such\plain\cf1\f51\fs20\ql patents against us or, if the holder did, that the courts would not interpret the claims of such patents more broadly\plain\cf1\f51\fs20\ql than we believe appropriate and determine that we are in infringement of such patents. In addition, there may be\plain\cf1\f51\fs20\ql other patents and patent applications related to our current or future{\*\bkmkstart _cp_text_1_331_12112272}{\*\bkmkend _cp_text_1_331_12112272}\plain\cf1\f51\fs20\ql drug candidates of which we are not aware.\plain\cf1\f51\fs20\ql Therefore, in some cases, in order to develop, manufacture, sell or import some of our{\*\bkmkstart _cp_text_1_333_12112272}{\*\bkmkend _cp_text_1_333_12112272}\plain\cf1\f51\fs20\ql drug candidates, we or our\plain\cf1\f51\fs20\ql collaborators may choose to seek, or be required to seek, licenses under third-party patents issued in the United\plain\cf1\f51\fs20\ql States and abroad or under third-party patents that might issue from U.S. and foreign patent applications. In such an\plain\cf1\f51\fs20\ql event, we would be required to pay license fees or royalties or both to the licensor. If licenses are not available to\plain\cf1\f51\fs20\ql us on acceptable terms, we or our collaborators may not be able to develop, manufacture, sell or import these\plain\cf1\f51\fs20\ql products, or may be delayed in doing so. Either of these results could have a material adverse effect on our\plain\cf1\f51\fs20\ql business.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We may become involved in expensive patent litigation or other proceedings, which could result in our incurring\plain\cf1\f51\fs20\b\i\qj substantial costs and expenses or substantial liability for damages, require us to stop our development and\plain\cf1\f51\fs20\b\i\qj commercialization efforts or result in our patents being invalidated, interpreted narrowly or limited.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql There has been substantial litigation and other proceedings regarding patent and other intellectual property\plain\cf1\f51\fs20\ql rights in the biotechnology industry. We may become a party to various types of patent litigation or other\plain\cf1\f51\fs20\ql proceedings regarding intellectual property rights from time to time even under circumstances where we are not\plain\cf1\f51\fs20\ql practicing and do not intend to practice any of the intellectual property involved in the proceedings.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition to litigation, we may become involved in patent office proceedings, including oppositions,\plain\cf1\f51\fs20\ql reexaminations, supplemental examinations and inter partes reviews involving our patents or the patents of third\plain\cf1\f51\fs20\ql parties. We may initiate such proceedings or have such proceedings brought against us. An adverse determination in\plain\cf1\f51\fs20\ql any such proceeding, or in litigation, could reduce the scope of, or invalidate, our patent rights, allow third parties\plain\cf1\f51\fs20\ql to commercialize our technology or products and compete directly with us, without payment to us, or result in our\plain\cf1\f51\fs20\ql inability to manufacture or commercialize products without infringing third-party patent rights. In addition, if the\plain\cf1\f51\fs20\ql breadth or strength of protection provided by our patents and patent applications is threatened, it could dissuade\plain\cf1\f51\fs20\ql companies from collaborating with us to license, develop or commercialize current or future drug candidates. An\plain\cf1\f51\fs20\ql adverse determination in a proceeding involving a patent in our portfolio could result in the loss of protection or a\plain\cf1\f51\fs20\ql narrowing in the scope of protection provided by that patent.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The cost to us of any patent litigation or other proceeding, even if resolved in our favor, could be substantial.\plain\cf1\f51\fs20\ql Some of our competitors may be able to sustain the cost of such litigation or proceedings more effectively than we\plain\cf1\f51\fs20\ql can because of their substantially greater financial resources. If any patent litigation or other proceeding is resolved\plain\cf1\f51\fs20\ql against us, we or our collaborators may be enjoined from developing, manufacturing, selling or importing our drugs\plain\cf1\f51\fs20\ql without a license from the other party and we may be held liable for significant damages. We may not be able to\plain\cf1\f51\fs20\ql obtain any required license on commercially acceptable terms or at all. In a patent office proceeding, such as an\plain\cf1\f51\fs20\ql opposition, reexamination or inter partes review, our patents may be narrowed or invalidated.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could\plain\cf1\f51\fs20\ql have a material adverse effect on our ability to compete in the marketplace. Patent litigation and other proceedings\plain\cf1\f51\fs20\ql may also absorb significant management time.\par\pard\plain\sb528\cf1\f51\fs20\qc 54\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_335_12112272}{\*\bkmkend _cp_text_1_335_12112272}\par\pard\plain\cf1\f51\fs20\b\qc Risks Relating to Product Manufacturing, Marketing and Sales, and Reliance on Third Parties\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\i\qj Because we have limited manufacturing experience, and no manufacturing facilities or infrastructure, we are\plain\cf1\f51\fs20\b\i\qj dependent on third-party manufacturers to manufacture drug candidates for us. If we cannot rely on third-party\plain\cf1\f51\fs20\b\i\qj manufacturers, we will be required to incur significant costs and devote significant efforts to establish our own\plain\cf1\f51\fs20\b\i\qj manufacturing facilities and capabilities.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have limited manufacturing experience and no manufacturing facilities, infrastructure or clinical or\plain\cf1\f51\fs20\ql commercial scale manufacturing capabilities. In order to continue to develop our drug candidates, apply for\plain\cf1\f51\fs20\ql regulatory approvals, and ultimately commercialize products, we need to develop, contract for or otherwise arrange\plain\cf1\f51\fs20\ql for the necessary manufacturing capabilities.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We currently rely upon third parties to produce material for nonclinical and clinical testing purposes and\plain\cf1\f51\fs20\ql expect to continue to do so in the future. We also expect to rely upon third parties to produce materials that may be\plain\cf1\f51\fs20\ql required for the commercial production of our drug candidates, if approved. Our current and anticipated future\plain\cf1\f51\fs20\ql dependence upon others for the manufacture of our drug candidates may adversely affect our future profit margins\plain\cf1\f51\fs20\ql and our ability to develop drug candidates and commercialize any drug candidates on a timely and competitive\plain\cf1\f51\fs20\ql basis. We currently do not have any long term supply contracts.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql There are a limited number of manufacturers that operate under the FDA's cGMP regulations capable of\plain\cf1\f51\fs20\ql manufacturing our drug candidates. As a result, we may have difficulty finding manufacturers for our drug\plain\cf1\f51\fs20\ql candidates with adequate capacity for our needs. If we are unable to arrange for third-party manufacturing of our\plain\cf1\f51\fs20\ql drug candidates on a timely basis, or to do so on commercially reasonable terms, we may not be able to complete\plain\cf1\f51\fs20\ql development of our drug candidates or market them.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Reliance on third-party manufacturers entails risks to which we would not be subject if we manufactured\plain\sa132\cf1\f51\fs20\ql drug candidates ourselves, including:
\par\pard\plain
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj reliance upon third-party manufacturers to assist us in preventing inadvertent disclosure or theft of our\plain\intbl\cf1\f51\fs20\qj proprietary knowledge.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Any contract manufacturers with which we enter into manufacturing arrangements will be subject to ongoing\plain\cf1\f51\fs20\ql periodic, unannounced inspections by the FDA, or foreign equivalent, and corresponding state and foreign agencies\plain\cf1\f51\fs20\ql or their designees to ensure compliance with cGMP requirements and other governmental regulations and\plain\cf1\f51\fs20\ql corresponding foreign standards. Any failure by our third-party manufacturers to comply with such requirements,\plain\cf1\f51\fs20\ql regulations or standards could lead to a delay in the conduct of our clinical trials, or a delay in, or failure to obtain,\plain\cf1\f51\fs20\ql regulatory approval of any of our drug candidates. Such failure could also result in sanctions being imposed,\plain\cf1\f51\fs20\ql including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, product seizures or\plain\cf1\f51\fs20\ql recalls, imposition of operating restrictions, total or partial suspension of production or distribution, or criminal\plain\cf1\f51\fs20\ql prosecution.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Additionally, contract manufacturers may not be able to manufacture our drug candidates at a cost or in\plain\cf1\f51\fs20\ql quantities necessary to make them commercially viable. As of February 15, 2018, our third-party manufacturers\plain\cf1\f51\fs20\ql have met our manufacturing requirements, but we cannot be assured that they will continue to do so. Furthermore,\plain\cf1\f51\fs20\ql changes in the manufacturing process or procedure, including a change in the location where the drug substance or\plain\cf1\f51\fs20\ql drug product is manufactured or a change of a third-party manufacturer, may require prior FDA review and\plain\cf1\f51\fs20\ql approval in accordance with the FDA's cGMP and New Drug Application/biologics license application regulations.\par\pard\plain\sb528\cf1\f51\fs20\qc 55\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql Contract manufacturers may also be subject to comparable foreign requirements. This review may be costly and\plain\cf1\f51\fs20\ql time-consuming and could delay or prevent the launch of a drug candidate. The FDA or similar foreign regulatory\plain\cf1\f51\fs20\ql agencies at any time may also implement new standards, or change their interpretation and enforcement of existing\plain\cf1\f51\fs20\ql standards for manufacture, packaging or testing of products. If we or our contract manufacturers are unable to\plain\cf1\f51\fs20\ql comply, we or they may be subject to regulatory action, civil actions or penalties.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We have no experience selling, marketing or distributing products and no internal capability to do so.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql If we receive regulatory approval to commence commercial sales of any of our drug candidates, we will face\plain\cf1\f51\fs20\ql competition with respect to commercial sales, marketing, and distribution. These are areas in which we have no\plain\cf1\f51\fs20\ql experience. To market any of our drug candidates directly, we would need to develop a marketing and sales force\plain\cf1\f51\fs20\ql with technical expertise and with supporting distribution capability. In particular, we would need to recruit\plain\cf1\f51\fs20\ql experienced marketing and sales personnel. Alternatively, we could engage a pharmaceutical or other healthcare\plain\cf1\f51\fs20\ql company with an existing distribution system and direct sales force to assist us. However, to the extent we entered\plain\cf1\f51\fs20\ql into such arrangements, we would be dependent on the efforts of third parties. If we are unable to establish sales\plain\cf1\f51\fs20\ql and distribution capabilities, whether internally or in reliance on third parties, our business would suffer materially.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj If third parties on whom we rely for clinical trials do not perform as contractually required or as we expect, we\plain\cf1\f51\fs20\b\i\qj may not be able to obtain regulatory approval for or commercialize our drug candidates and our business may\plain\cf1\f51\fs20\b\i\qj suffer.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We do not have the ability to independently conduct the clinical trials required to obtain regulatory approval\plain\cf1\f51\fs20\ql for our drug candidates. We depend on independent clinical investigators, contract research organizations, and other\plain\cf1\f51\fs20\ql third-party service providers in the conduct of the clinical trials of our drug candidates and expect to continue to do\plain\cf1\f51\fs20\ql so. We have contracted with contract research organizations to manage our ongoing clinical trials of IMO-2125 and\plain\cf1\f51\fs20\ql IMO-8400 and expect to contract with such organizations for future clinical trials. We rely heavily on these parties\plain\cf1\f51\fs20\ql for successful execution of our clinical trials, but do not control many aspects of their activities. We are responsible\plain\cf1\f51\fs20\ql for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and\plain\cf1\f51\fs20\ql protocols for the trial. Moreover, the FDA and foreign regulatory agencies require us to comply with certain\plain\cf1\f51\fs20\ql standards, commonly referred to as good clinical practices, and applicable regulatory requirements, for conducting,\plain\cf1\f51\fs20\ql recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate\plain\cf1\f51\fs20\ql and that the rights, integrity, and confidentiality of clinical trial participants are protected. Our reliance on third\plain\cf1\f51\fs20\ql parties that we do not control does not relieve us of these responsibilities and requirements. Third parties may not\plain\cf1\f51\fs20\ql complete activities on schedule, or at all, or may not conduct our clinical trials in accordance with regulatory\plain\cf1\f51\fs20\ql requirements or our stated protocols. If these third parties fail to carry out their obligations, we may need to enter\plain\cf1\f51\fs20\ql into new arrangements with alternative third parties. This could be difficult, costly or impossible, and our preclinical\plain\cf1\f51\fs20\ql studies or clinical trials may need to be extended, delayed, terminated or repeated, and we may not be able to\plain\cf1\f51\fs20\ql obtain regulatory approval in a timely fashion, or at all, for the applicable drug candidate, or to commercialize such\plain\cf1\f51\fs20\ql drug candidate being tested in such studies or trials. If we seek to conduct any of these activities ourselves in the\plain\cf1\f51\fs20\ql future, we will need to recruit appropriately trained personnel and add to our research, clinical, quality and\plain\cf1\f51\fs20\ql corporate infrastructure.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj The commercial success of any drug candidates that we may develop will depend upon the degree of market\plain\cf1\f51\fs20\b\i\qj acceptance by physicians, patients, third-party payors, and others in the medical community.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Any products that we ultimately bring to the market, if they receive marketing approval, may not gain market\plain\cf1\f51\fs20\ql acceptance by physicians, patients, third-party payors or others in the medical community. For example, current\plain\cf1\f51\fs20\ql cancer treatments like chemotherapy and radiation therapy are well established in the medical community, and\plain\cf1\f51\fs20\ql doctors may continue to rely on these treatments. If our products do not achieve an adequate level of acceptance,\plain\cf1\f51\fs20\ql we may not generate product revenue and we may not become profitable. The degree of market acceptance of our\plain\sa132\cf1\f51\fs20\ql products, if approved for commercial sale, will depend on a number of factors, including:
\par\pard\plain
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\qj the efficacy and potential advantages over alternative treatments;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\qj the ability to offer our drug candidates for sale at competitive prices;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh382\row}}}\pard\plain\sb528\cf1\f51\fs20\qc 56\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the willingness of the target patient population to try new therapies and of physicians to prescribe these\plain\intbl\sa132\cf1\f51\fs20\qj therapies;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the strength of marketing and distribution support and the timing of market introduction of\plain\intbl\sa132\cf1\f51\fs20\qj competitive products; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj publicity concerning our products or competing products and treatments.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\li1188\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\qj Even if a potential product displays a favorable efficacy and safety profile, market acceptance of the product\plain\cf1\f51\fs20\qj will not be known until after it is launched. Our efforts to educate patients, the medical community, and third-party\plain\cf1\f51\fs20\qj payors on the benefits of our drug candidates may require significant resources and may never be successful. Such\plain\cf1\f51\fs20\qj efforts to educate the marketplace may require more resources than are required by conventional technologies\plain\cf1\f51\fs20\qj marketed by our competitors.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\qj If we are unable to obtain adequate reimbursement from third-party payors for any products that we may\plain\cf1\f51\fs20\b\i\qj develop or acceptable prices for those products, our revenues and prospects for profitability will suffer.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Most patients rely on Medicare, Medicaid, private health insurers, and other third-party payors to pay for\plain\cf1\f51\fs20\ql their medical needs, including any drugs we may market. If third-party payors do not provide adequate coverage or\plain\cf1\f51\fs20\ql reimbursement for any products that we may develop, our revenues and prospects for profitability will suffer.\plain\cf1\f51\fs20\ql Congress enacted a limited prescription drug benefit for Medicare recipients in the Medicare Prescription Drug,\plain\cf1\f51\fs20\ql Improvement, and Modernization Act of 2003. While the program established by this statute may increase demand\plain\cf1\f51\fs20\ql for our products if we were to participate in this program, our prices will be negotiated with drug procurement\plain\cf1\f51\fs20\ql organizations for Medicare beneficiaries and are likely to be lower than we might otherwise obtain. Non-Medicare\plain\cf1\f51\fs20\ql third-party drug procurement organizations may also base the price they are willing to pay on the rate paid by drug\plain\cf1\f51\fs20\ql procurement organizations for Medicare beneficiaries or may otherwise negotiate the price they are willing to pay.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql A primary trend in the United States healthcare industry is toward cost containment. In addition, in some\plain\cf1\f51\fs20\ql foreign countries, particularly the countries of the European Union, the pricing of prescription pharmaceuticals is\plain\cf1\f51\fs20\ql subject to governmental control. In these countries, pricing negotiations with governmental authorities can take six\plain\cf1\f51\fs20\ql months or longer after the receipt of regulatory marketing approval for a product. To obtain reimbursement or\plain\cf1\f51\fs20\ql pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost\plain\cf1\f51\fs20\ql effectiveness of our drug candidates or products to other available therapies. The conduct of such a clinical trial\plain\cf1\f51\fs20\ql could be expensive and result in delays in commercialization of our drug candidates. These further clinical trials\plain\cf1\f51\fs20\ql would require additional time, resources, and expenses. If reimbursement of our products is unavailable or limited in\plain\cf1\f51\fs20\ql scope or amount, or if pricing is set at unsatisfactory levels, our prospects for generating revenue, if any, could be\plain\cf1\f51\fs20\ql adversely affected and our business may suffer.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In March 2010, the Patient Protection and Affordable Care Act and the Health Care and Education\plain\cf1\f51\fs20\ql Reconciliation Act became law. These health care reform laws are intended to broaden access to health insurance;\plain\cf1\f51\fs20\ql reduce or constrain the growth of health care spending, especially Medicare spending; enhance remedies against\plain\cf1\f51\fs20\ql fraud and abuse; add new transparency requirements for health care and health insurance industries; impose new\plain\cf1\f51\fs20\ql taxes and fees on certain sectors of the health industry; and impose additional health policy reforms. Among the\plain\cf1\f51\fs20\ql new fees is an annual assessment on makers of branded pharmaceuticals and biologics, under which a company's\plain\cf1\f51\fs20\ql assessment is based primarily on its share of branded drug sales to federal health care programs. Such fees could\plain\cf1\f51\fs20\ql affect our future prospects for profitability. Although it is too early to determine the effect of the health care\plain\cf1\f51\fs20\ql legislation on our future prospects for profitability and financial condition, the law appears likely to continue the\plain\cf1\f51\fs20\ql pressure on pharmaceutical pricing, especially under the Medicare program, and may also increase our regulatory\plain\cf1\f51\fs20\ql burdens and operating costs.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Third-party payors are challenging the prices charged for medical products and services, and many\plain\cf1\f51\fs20\ql third-party payors limit reimbursement for newly-approved health care products. These third-party payors may\plain\cf1\f51\fs20\ql base their coverage and reimbursement on the coverage and reimbursement rate paid by carriers for Medicare\plain\cf1\f51\fs20\ql beneficiaries. Furthermore, many such payors are investigating or implementing methods for reducing health care\plain\cf1\f51\fs20\ql costs, such as the establishment of capitated or prospective payment systems. Cost containment pressures have led\plain\cf1\f51\fs20\ql to an increased emphasis on the use of cost-effective products by health care providers. In particular, third-party\plain\cf1\f51\fs20\ql payors may limit the indications for which they will reimburse patients who use any products that we may develop.\plain\cf1\f51\fs20\ql Cost control initiatives could limit the price we might establish for products that we or our current or future\plain\cf1\f51\fs20\ql collaborators may develop or sell, which would result in lower product revenues or royalties payable to us.\par\pard\plain\sb528\cf1\f51\fs20\qc 57\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj We face a risk of product liability claims and may not be able to obtain insurance.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our business exposes us to the risk of product liability claims that is inherent in the manufacturing, testing,\plain\cf1\f51\fs20\ql and marketing of human therapeutic drugs. We face an inherent risk of product liability exposure related to the\plain\cf1\f51\fs20\ql testing of our drug candidates in human clinical trials and will face an even greater risk if we commercially sell any\plain\sa132\cf1\f51\fs20\ql products. Regardless of merit or eventual outcome, liability claims and product recalls may result in:
\par\pard\plain
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1148
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the inability to commercialize any products that we may develop.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Although we have product liability and clinical trial liability insurance that we believe is adequate, this\plain\cf1\f51\fs20\ql insurance is subject to deductibles and coverage limitations. We may not be able to obtain or maintain adequate\plain\cf1\f51\fs20\ql protection against potential liabilities. If we are unable to obtain insurance at acceptable cost or otherwise protect\plain\cf1\f51\fs20\ql against potential product liability claims, we will be exposed to significant liabilities, which may materially and\plain\cf1\f51\fs20\ql adversely affect our business and financial position. These liabilities could prevent or interfere with our\plain\sa132\cf1\f51\fs20\ql commercialization efforts.{\*\bkmkstart _cp_text_1_339_12112272}{\*\bkmkend _cp_text_1_339_12112272}\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\qc Risks Relating to Ownership of Our Common Stock\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\cf1\f51\fs20\b\i\qj Our corporate governance structure, including provisions in our certificate of incorporation and by-laws and\plain\cf1\f51\fs20\b\i\qj Delaware law, may prevent a change in control or management that stockholders may consider desirable.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Section 203 of the Delaware General Corporation Law and our certificate of incorporation and by-laws\plain\cf1\f51\fs20\ql contain provisions that might enable our management to resist a takeover of our company or discourage a third\plain\sa132\cf1\f51\fs20\ql party from attempting to take over our company. These provisions include:
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\qj ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qj the ability of our board of directors to designate the terms of and issue new series of preferred stock\plain\intbl\cf1\f51\fs20\qj without stockholder approval.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, Section 203 of the Delaware General Corporation Law imposes restrictions on our ability to\plain\cf1\f51\fs20\ql engage in business combinations and other specified transactions with significant stockholders. These provisions\plain\cf1\f51\fs20\ql could have the effect of delaying, deferring or preventing a change in control of us or a change in our management\plain\cf1\f51\fs20\ql that stockholders may consider favorable or beneficial. These provisions could also discourage proxy contests and\plain\cf1\f51\fs20\ql make it more difficult for you and other stockholders to elect directors and take other corporate actions. These\plain\cf1\f51\fs20\ql provisions could also limit the price that investors might be willing to pay in the future for shares of our common\plain\cf1\f51\fs20\ql stock.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 58\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\i\qj We have two significant securityholders. If these securityholders choose to act together, they could exert\plain\cf1\f51\fs20\b\i\qj substantial influence over our business. In addition, in connection with any merger, consolidation or sale of all\plain\cf1\f51\fs20\b\i\qj or substantially all of our assets, they would be entitled to receive consideration in excess of their reported\plain\cf1\f51\fs20\b\i\qj beneficial ownership of our common stock.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of February 15, 2018, Baker Bros. Advisors LP, and certain of its affiliated funds, which we refer to\plain\cf1\f51\fs20\ql collectively as Baker Brothers, held 18,325,135 shares of our common stock, warrants to purchase up to 20,316,327\plain\cf1\f51\fs20\ql shares of our common stock at an exercise price of $0.47 per share and pre-funded warrants to purchase up to\plain\cf1\f51\fs20\ql 22,151,052 shares of our common stock at an exercise price of $0.01 per share. In addition, two members of our\plain\cf1\f51\fs20\ql board of directors are affiliates of Baker Brothers. Under the terms of the warrants and pre-funded warrants issued\plain\cf1\f51\fs20\ql to Baker Brothers, Baker Brothers is not permitted to exercise such warrants to the extent that such exercise would\plain\cf1\f51\fs20\ql result in Baker Brothers (and its affiliates) beneficially owning more than 4.999% of the number of shares of our\plain\cf1\f51\fs20\ql common stock outstanding immediately after giving effect to the issuance of shares of common stock issuable upon\plain\cf1\f51\fs20\ql exercise of such warrants. Baker Brothers has the right to increase this beneficial ownership limitation in its\plain\cf1\f51\fs20\ql discretion on 61 days' prior written notice to us, provided that in no event is Baker Brothers permitted to exercise\plain\cf1\f51\fs20\ql such warrants to the extent that such exercise would result in Baker Brothers (and its affiliates) beneficially owning\plain\cf1\f51\fs20\ql more than 19.99% of the number of shares of our common stock outstanding or the combined voting power of our\plain\cf1\f51\fs20\ql securities outstanding immediately after giving effect to the issuance of shares of common stock issuable upon\plain\cf1\f51\fs20\ql exercise of such warrants. On March 5, 2018, Baker Brothers provided us such 61 days\u8217? notice in regards to\plain\cf1\f51\fs20\ql the above mentioned warrants to purchase up to 20,316,327 shares of our common stock at an exercise price of\plain\cf1\f51\fs20\ql $0.47 per share. After giving effect to the 4.999% beneficial ownership limitation currently in effect with respect to\plain\cf1\f51\fs20\ql the warrants and pre-funded warrants held by Baker Brothers, as of February 15, 2018, Baker Brothers beneficially\plain\cf1\f51\fs20\ql owned 9.5% of our outstanding common stock. If the warrants and pre-funded warrants held by Baker Brothers\plain\cf1\f51\fs20\ql could be exercised without this limitation, then as of February 15, 2018, Baker Brothers would have beneficially\plain\cf1\f51\fs20\ql owned 25.6% of our common stock. The information in this paragraph is based on a Schedule 13D/A filed with the\plain\cf1\f51\fs20\ql SEC on October 30, 2017; a Form 4 filed with the SEC on January 4, 2018; and on information provided to us by\plain\cf1\f51\fs20\ql Baker Brothers. On February 9, 2015, we entered into a registration rights agreement with Baker Brothers, pursuant\plain\cf1\f51\fs20\ql to which we agreed to file registration statements to register for resale the shares of our common stock, including\plain\cf1\f51\fs20\ql shares issuable upon the exercise of warrants, held by Baker Brothers\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of February 15, 2018, entities affiliated with Pillar Invest Corporation, which we refer to collectively as\plain\cf1\f51\fs20\ql the Pillar Investment Entities, held 25,413,574 shares of our common stock and warrants to purchase up to\plain\cf1\f51\fs20\ql 1,200,000 shares of our common stock at an exercise price of $0.47 per share. As of February 15, 2018, the Pillar\plain\cf1\f51\fs20\ql Investment Entities beneficially owned 13.6% of our outstanding common stock.\~\~The Pillar Investment Entities are\plain\cf1\f51\fs20\ql subject to contractual limitations that limit their ability to exercise any securities held by them that are exercisable\plain\cf1\f51\fs20\ql into shares of our common stock to the extent that such exercise would result in the Pillar Investment Entities and\plain\cf1\f51\fs20\ql their affiliates beneficially owning more than 19.99% of the number of shares of our common stock outstanding or\plain\cf1\f51\fs20\ql the combined voting power of our securities outstanding immediately after giving effect to the issuance of shares of\plain\cf1\f51\fs20\ql common stock issuable upon exercise of such securities.\~\~The information in this paragraph is based on{\*\bkmkstart _cp_text_1_348_12112272}{\*\bkmkend _cp_text_1_348_12112272}\plain\cf1\f51\fs20\ql a Schedule\plain\cf1\f51\fs20\ql 13D/A filed with the SEC on October 17, 2016; Form 4s filed with the SEC on May 3, 2017, October 17, 2017,\plain\cf1\f51\fs20\ql December 15, 2017 and January 19, 2018; and on information provided to us by Pillar Invest Corporation.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Although there are contractual limitations on the beneficial ownership of Baker Brothers and the Pillar\plain\cf1\f51\fs20\ql Investment Entities, which we refer to collectively as our significant securityholders, if our significant\plain\cf1\f51\fs20\ql securityholders were to exercise their warrants for common stock and were to choose to act together, they could be\plain\cf1\f51\fs20\ql able to exert substantial influence over our business. This concentration of voting power could delay, defer or\plain\cf1\f51\fs20\ql prevent a change of control, entrench our management and the board of directors or delay or prevent a merger,\plain\cf1\f51\fs20\ql consolidation, takeover or other business combination involving us on terms that other stockholders may desire. In\plain\cf1\f51\fs20\ql addition, conflicts of interest could arise in the future between us, on the one hand, and either or both of our\plain\cf1\f51\fs20\ql significant securityholders on the other hand, concerning potential competitive business activities, business\plain\cf1\f51\fs20\ql opportunities, the issuance of additional securities and other matters. Furthermore in the event of a sale of our\plain\cf1\f51\fs20\ql company, whether by merger, sale of all or substantially all of our assets or otherwise, our significant\plain\cf1\f51\fs20\ql securityholders would be entitled to receive, with respect to each share of common stock issuable upon exercise of\plain\cf1\f51\fs20\ql the warrants then held by them and without regard to the beneficial ownership limitations imposed on the\plain\cf1\f51\fs20\ql conversion or exercise of such securities, the same amount and kind of securities, cash or property as they would\plain\cf1\f51\fs20\ql have been entitled to receive if such securities had been converted into or exercised for shares of our common stock\plain\cf1\f51\fs20\ql immediately prior to such sale of our company. Because the significant securityholders would receive this sale\plain\cf1\f51\fs20\ql consideration with respect to warrants not included in their reported beneficial ownership of our common\par\pard\plain\sb528\cf1\f51\fs20\qc 59\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql stock, in the event of a sale of our company, they would be entitled to receive a significantly larger portion of the\plain\cf1\f51\fs20\ql total proceeds distributable to the holders of our securities than is represented by their reported beneficial ownership\plain\cf1\f51\fs20\ql of our common stock.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\qj Our stock price has been and may in the future be extremely volatile. In addition, because our common stock\plain\cf1\f51\fs20\b\i\qj has historically been traded at low volume levels, our investors' ability to trade our common stock may be\plain\cf1\f51\fs20\b\i\qj limited. As a result, investors may lose all or a significant portion of their investment.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our stock price has been and may in the future be volatile. During the period from January 1, 2017 to\plain\cf1\f51\fs20\ql February 15, 2018, the closing sales price of our common stock ranged from a high of $2.87 per share to a low of\plain\cf1\f51\fs20\ql $1.30 per share. The stock market has also experienced periods of significant price and volume fluctuations and the\plain\cf1\f51\fs20\ql market prices \~of biotechnology companies in particular have been highly volatile, often for reasons that have been\plain\cf1\f51\fs20\ql unrelated to the operating performance of particular companies. The market price for our common stock may be\plain\sa132\cf1\f51\fs20\ql influenced by many factors, including:
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql our success in entering into collaborative agreements;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql developments or disputes concerning patents or other proprietary rights;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql the departure of key personnel;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql our ability to maintain the listing of our common stock on The Nasdaq Capital Market or an\plain\intbl\sa132\cf1\f51\fs20\ql alternative national securities exchange;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql variations in our financial results or those of companies that are perceived to be similar to us;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql the terms of any financing consummated by us;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f51\fs20\ql changes in the structure of healthcare payment systems;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh405\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql market conditions in the pharmaceutical and biotechnology sectors and issuance of new or changed\plain\intbl\sa132\cf1\f51\fs20\ql securities analysts' reports or recommendations; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
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{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql general economic, industry, and market conditions.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\li1188\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In addition, our common stock has historically been traded at low volume levels and may continue to trade at\plain\cf1\f51\fs20\ql low volume levels. As a result, any large purchase or sale of our common stock could have a significant impact on\plain\cf1\f51\fs20\ql the price of our common stock and it may be difficult for investors to sell our common stock in the market without\plain\cf1\f51\fs20\ql depressing the market price for the common stock or at all.\par\pard\plain\fi594\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_518_12112272}{\*\bkmkend _cp_text_1_518_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql The announcement and pendency of the Mergers, whether or not consummated, may adversely affect the{\*\bkmkstart _cp_text_4_519_12112272}{\*\bkmkend _cp_text_4_519_12112272}\plain\cf1\f51\fs20\ql trading price of{\*\bkmkstart _cp_text_1_520_12112272}{\*\bkmkend _cp_text_1_520_12112272}\plain\cf1\f51\fs20\ql our common stock and our business prospects. In the event that the Mergers are not completed, the\plain\cf1\f51\fs20\ql announcement of the termination of the Merger Agreement may also adversely affect the trading price of our\plain\cf1\f51\fs20\ql common stock and our business prospects.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As a result of the foregoing, investors may not be able to resell their shares at or above the price they paid\plain\cf1\f51\fs20\ql for such shares. Investors in our common stock must be willing to bear the risk of fluctuations in the price of our\plain\cf1\f51\fs20\ql common stock and the risk that the value of their investment in our stock could decline.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 60\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\i\qj Because we do not intend to pay dividends on our common stock, investor returns will be limited to any increase\plain\cf1\f51\fs20\b\i\qj in the value of our stock.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have never declared or paid any cash dividends on our common stock. In addition, under the terms of our\plain\cf1\f51\fs20\ql loan and security agreement with Oxford Finance LLC, we are required to obtain the prior written consent of\plain\cf1\f51\fs20\ql Oxford Finance LLC in order to declare or pay a cash dividend on our common stock in an amount in excess of\plain\cf1\f51\fs20\ql $500,000 in any fiscal year. We currently intend to retain all available funds and any future earnings to support our\plain\cf1\f51\fs20\ql operations and finance the growth and development of our business and do not anticipate declaring or paying any\plain\cf1\f51\fs20\ql cash dividends on our common stock for the foreseeable future. Any return to stockholders will therefore be limited\plain\cf1\f51\fs20\ql to the appreciation of their stock, if any.\~\par\pard\plain\fi528\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_521_12112272}{\*\bkmkend _cp_text_1_521_12112272}\par\pard\plain\cf1\f51\fs20\b\i\ql Our stockholders approved an amendment to our certificate of incorporation that allows our{\*\bkmkstart _cp_text_4_522_12112272}{\*\bkmkend _cp_text_4_522_12112272}\plain\cf1\f51\fs20\b\i\ql board of directors{\*\bkmkstart _cp_text_1_523_12112272}{\*\bkmkend _cp_text_1_523_12112272}\plain\cf1\f51\fs20\b\i\ql to effect a reverse stock split by a ratio within a specified range, which reverse stock split, if implemented, may\plain\cf1\f51\fs20\b\i\ql not achieve one or more of our objectives.\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_524_12112272}{\*\bkmkend _cp_text_1_524_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql There can be no assurance that the market price per new share of our common stock after a reverse stock\plain\cf1\f51\fs20\ql split will remain unchanged or increase in proportion{\*\bkmkstart _cp_text_4_525_12112272}{\*\bkmkend _cp_text_4_525_12112272}\plain\cf1\f51\fs20\ql to the{\*\bkmkstart _cp_text_1_526_12112272}{\*\bkmkend _cp_text_1_526_12112272}\plain\cf1\f51\fs20\ql reduction in{\*\bkmkstart _cp_text_4_527_12112272}{\*\bkmkend _cp_text_4_527_12112272}\plain\cf1\f51\fs20\ql the number of shares of{\*\bkmkstart _cp_text_1_528_12112272}{\*\bkmkend _cp_text_1_528_12112272}\plain\cf1\f51\fs20\ql our common stock\plain\cf1\f51\fs20\ql outstanding before the reverse stock split. The market{\*\bkmkstart _cp_text_4_529_12112272}{\*\bkmkend _cp_text_4_529_12112272}\plain\cf1\f51\fs20\ql price of{\*\bkmkstart _cp_text_1_530_12112272}{\*\bkmkend _cp_text_1_530_12112272}\plain\cf1\f51\fs20\ql our shares may fluctuate and potentially decline after\plain\cf1\f51\fs20\ql a reverse stock split. Accordingly, the total market capitalization of our common stock after a reverse stock split, if\plain\cf1\f51\fs20\ql implemented, may be lower than the total market capitalization before the reverse stock split. Moreover{\*\bkmkstart _cp_text_4_531_12112272}{\*\bkmkend _cp_text_4_531_12112272}\plain\cf1\f51\fs20\ql , in the{\*\bkmkstart _cp_text_1_532_12112272}{\*\bkmkend _cp_text_1_532_12112272}\plain\cf1\f51\fs20\ql future, the market price of our common stock following a reverse stock split may not exceed or remain higher than\plain\cf1\f51\fs20\ql the market price{\*\bkmkstart _cp_text_4_533_12112272}{\*\bkmkend _cp_text_4_533_12112272}\plain\cf1\f51\fs20\ql prior to the{\*\bkmkstart _cp_text_1_534_12112272}{\*\bkmkend _cp_text_1_534_12112272}\plain\cf1\f51\fs20\ql reverse stock split.\par\pard\plain\fi594\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_4_535_12112272}{\*\bkmkend _cp_text_4_535_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql In addition,{\*\bkmkstart _cp_text_1_536_12112272}{\*\bkmkend _cp_text_1_536_12112272}\plain\cf1\f51\fs20\ql while our board of directors believes that a higher stock price may help generate investor\plain\cf1\f51\fs20\ql interest, there can be no assurance that a reverse stock split{\*\bkmkstart _cp_text_4_537_12112272}{\*\bkmkend _cp_text_4_537_12112272}\plain\cf1\f51\fs20\ql will result in{\*\bkmkstart _cp_text_1_538_12112272}{\*\bkmkend _cp_text_1_538_12112272}\plain\cf1\f51\fs20\ql a per-share market price that will attract\plain\cf1\f51\fs20\ql institutional investors or investment funds or that such share price will satisfy the investing guidelines of\plain\cf1\f51\fs20\ql institutional investors or investment funds. As a result, the trading liquidity of our common stock may not\plain\cf1\f51\fs20\ql necessarily improve. Further, if a reverse stock split is effected and the market price of our common stock declines,\plain\cf1\f51\fs20\ql the percentage decline may be greater than would occur in the absence of a reverse stock split.\par\pard\plain\fi594\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_539_12112272}{\*\bkmkend _cp_text_1_539_12112272}\par\pard\plain\fi594\cf1\f51\fs20\ql Following{\*\bkmkstart _cp_text_4_540_12112272}{\*\bkmkend _cp_text_4_540_12112272}\plain\cf1\f51\fs20\ql the reverse stock split{\*\bkmkstart _cp_text_1_541_12112272}{\*\bkmkend _cp_text_1_541_12112272}\plain\cf1\f51\fs20\ql , if implemented, the number of our outstanding shares will be reduced by a\plain\cf1\f51\fs20\ql whole number factor ranging from four to eight, which may lead to reduced trading and a smaller number of market\plain\cf1\f51\fs20\ql makers for our{\*\bkmkstart _cp_text_4_542_12112272}{\*\bkmkend _cp_text_4_542_12112272}\plain\cf1\f51\fs20\ql common stock{\*\bkmkstart _cp_text_1_543_12112272}{\*\bkmkend _cp_text_1_543_12112272}\plain\cf1\f51\fs20\ql . Brokerage firms often do not permit stocks trading below $5.00 per share to be sold\plain\cf1\f51\fs20\ql short, but permit short-selling of shares which are traded at higher prices. Following the reverse stock split, to the\plain\cf1\f51\fs20\ql extent our per-share trading price is consistently above $5.00, investors may short our stock. This may increase the\plain\cf1\f51\fs20\ql volatility of our stock price.\par\pard\plain\sa132\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_3}{\*\bkmkend item_1_3_3}\par\pard\plain\cf11\f51\fs24\b\ql Item\~1B.\~\~\~\~Unresolved Staff Comments.{\*\bkmkstart item1bunresolvedstaffcomments_54}{\*\bkmkend item1bunresolvedstaffcomments_54}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql None.\par\pard\plain\sa66\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_4}{\*\bkmkend item_1_3_4}\par\pard\plain\cf11\f51\fs24\b\ql Item\~2.\~\~\~\~Properties.{\*\bkmkstart item2properties_204182_12112272}{\*\bkmkend item2properties_204182_12112272}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql We lease approximately 27,000\~square feet of laboratory and office space located in Cambridge,\plain\cf1\f51\fs20\ql Massachusetts. The lease expires on August\~31, 2022 subject to a five-year renewal option exercisable by us. We\plain\cf1\f51\fs20\ql also lease approximately 11,000\~square feet of office space located in Exton, Pennsylvania. The lease expires on\plain\cf1\f51\fs20\ql May 31, 2020 subject to a three-year renewal option exercisable by us. We have specified rights to sublease these\plain\cf1\f51\fs20\ql facilities.\par\pard\plain\sa66\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_5}{\*\bkmkend item_1_3_5}\par\pard\plain\cf11\f51\fs24\b\ql Item\~3.\~\~\~\~Legal Proceedings.{\*\bkmkstart item3legalproceedings_265422_121}{\*\bkmkend item3legalproceedings_265422_121}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql None.\par\pard\plain\sa132\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_6}{\*\bkmkend item_1_3_6}\par\pard\plain\cf11\f51\fs24\b\ql Item\~4.\~\~\~\~Mine Safety Disclosures.{\*\bkmkstart item4minesafetydisclosures_93711}{\*\bkmkend item4minesafetydisclosures_93711}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Not applicable.\par\pard\plain\sb528\cf1\f51\fs20\qc 61\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart part_1_2_2}{\*\bkmkend part_1_2_2}\par\pard\plain\cf11\f51\fs24\b\qc PART\~II.{\*\bkmkstart partii_599096_12112272}{\*\bkmkend partii_599096_12112272}\par\pard\plain\cf1\f51\fs20\qc \~{\*\bkmkstart item_1_3_7}{\*\bkmkend item_1_3_7}\par\pard\plain\li1210\fi-1210\cf11\f51\fs24\b\ql Item\~5.Market for Registrant\u8217?s Common Equity, Related Stockholder Matters and\plain\li1210\cf11\f51\fs24\b\ql Issuer Purchases of Equity{\*\bkmkstart item5marketforregistrantscommone}{\*\bkmkend item5marketforregistrantscommone}\plain\li1210\cf11\f51\fs24\b\ql Securities.\par\pard\plain\li1210\fi-1210\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Market Information\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Our common stock is listed under the symbol \u8220?IDRA\u8221? on the Nasdaq Capital Market.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql The following table sets forth, for the periods indicated, the high and low sales prices per share of our\plain\cf1\f51\fs20\ql common stock during each of the quarters set forth below as reported on the Nasdaq Capital Market.\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc High\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Low\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\b\ql 2016\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql First Quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 3.10\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1.50\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Fourth Quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2.66\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1.43\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\b\ql 2017\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql First Quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2.60\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1.30\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Third Quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2.39\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1.68\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Fourth Quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2.87\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1.32\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx7131\clvertalb\cellx7371\clvertalb\cellx7579\clvertalb\cellx8347\clvertalb\cellx8587\clvertalb\cellx8778\clvertalb\cellx9546\clvertalb\cellx9688\trrh248\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Holders of Record\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql As of February 15, 2018, we had approximately 92 common stockholders of record registered on our books,\plain\cf1\f51\fs20\ql excluding shares held through banks and brokers.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Dividends\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql We have never declared or paid cash dividends on our common stock, and we do not expect to pay any cash\plain\cf1\f51\fs20\ql dividends on our common stock in the foreseeable future. Under the terms of our loan and security agreement with\plain\cf1\f51\fs20\ql Oxford Finance LLC, we are required to obtain the prior written consent of Oxford Finance LLC in order to declare\plain\cf1\f51\fs20\ql or pay a cash dividend on our common stock in an amount in excess of $500,000 in any fiscal year.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Recent Sales of Unregistered Securities\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_557_12112272}{\*\bkmkend _cp_text_1_557_12112272}\par\pard\plain\fi550\cf1\f51\fs20\ql In October 2017, we issued 6,842,844 shares of our common stock in unregistered sales to holders of\plain\cf1\f51\fs20\ql warrants upon the exercise of such warrants.\~\~We issued the 6,842,844 shares upon the payment of a warrant\plain\cf1\f51\fs20\ql exercise price of $0.70 per share.\~\~We received approximately $4.8 million of cash proceeds in the aggregate upon\plain\cf1\f51\fs20\ql the exercise of the foregoing warrants.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql In December 2017, we issued 700,000 shares of our common stock in unregistered sales to a holder of\plain\cf1\f51\fs20\ql warrants upon the exercise of such warrants.\~\~We issued the 700,000 shares upon the payment of a warrant exercise\plain\cf1\f51\fs20\ql price of $0.47 per share.\~\~We received approximately $0.3 million of cash proceeds in the aggregate upon the\plain\cf1\f51\fs20\ql exercise of the foregoing warrants.\~\par\pard\plain\fi550\cf1\f51\fs20\ql \~{\*\bkmkstart _cp_text_1_560_12112272}{\*\bkmkend _cp_text_1_560_12112272}\par\pard\plain\fi550\cf1\f51\fs20\ql The issuance{\*\bkmkstart _cp_text_4_561_12112272}{\*\bkmkend _cp_text_4_561_12112272}\plain\cf1\f51\fs20\ql of shares of{\*\bkmkstart _cp_text_1_562_12112272}{\*\bkmkend _cp_text_1_562_12112272}\plain\cf1\f51\fs20\ql our common stock upon exercise of outstanding warrants described above were\plain\cf1\f51\fs20\ql exempt from registration under the{\*\bkmkstart _cp_text_4_563_12112272}{\*\bkmkend _cp_text_4_563_12112272}\plain\cf1\f51\fs20\ql Securities Act{\*\bkmkstart _cp_text_1_564_12112272}{\*\bkmkend _cp_text_1_564_12112272}\plain\cf1\f51\fs20\ql of 1933, as amended, and Rule 506 of Regulation D promulgated\plain\cf1\f51\fs20\ql thereunder as not involving a public offering.\~\~The shares of common stock issued by us upon these warrant\plain\cf1\f51\fs20\ql exercises have been registered for resale{\*\bkmkstart _cp_text_4_565_12112272}{\*\bkmkend _cp_text_4_565_12112272}\plain\cf1\f51\fs20\ql by the{\*\bkmkstart _cp_text_1_566_12112272}{\*\bkmkend _cp_text_1_566_12112272}\plain\cf1\f51\fs20\ql holders under our Registration Statement on Form S-3, File No.\plain\cf1\f51\fs20\ql 333-185392.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Issuer Purchases of Equity Securities\par\pard\plain\cf15\f51\fs17\ql \~\par\pard\plain\fi440\cf1\f51\fs20\ql We did not repurchase any of our equity securities during the year ended December 31, 2017.\par\pard\plain\sb528\cf1\f51\fs20\qc 62\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\ql Comparative Stock Performance\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\i\ql The information included under the heading \u8220?Comparative Stock Performance\u8221? in Item\~5 of this\plain\cf1\f51\fs20\i\ql Annual Report on Form 10-K is \u8220?furnished\u8221? and not \u8220?filed\u8221? and shall not be deemed to\plain\cf1\f51\fs20\i\ql be \u8220?soliciting material\u8221? or subject to Regulation 14A, shall not be deemed \u8220?filed\u8221? for\plain\cf1\f51\fs20\i\ql purposes of Section\~18 of the Exchange Act or otherwise subject to the liabilities of that section, nor shall it be\plain\cf1\f51\fs20\i\ql deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql The comparative stock performance graph shown below compares cumulative stockholder return on our\plain\cf1\f51\fs20\ql common stock from December\~31, 2012 through December\~31, 2017, with the cumulative total return of the Russell\plain\cf1\f51\fs20\ql 2000 Index and the Nasdaq Biotechnology Index. This graph assumes an investment of $100 on December\~31, 2012\plain\cf1\f51\fs20\ql in our common stock and in each of the indices and assumes that dividends are reinvested.\par\pard\plain\sa132\cf13\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs24\b\qc COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN\par\pard\plain\fi550\cf1\f51\fs20\qc Among Idera Pharmaceuticals, Inc., the Russell 2000 Index\par\pard\plain\fi550\cf1\f51\fs20\qc and the Nasdaq Biotechnology Index\par\pard\plain\cf13\f51\fs20\ql \~\par\qc{\*\shppict{\pict\pngblip\picw789\pich457\picscalex61\picscaley61\bliptag-32101099673
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\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\qc \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 12/31/12\cell\pard\plain\intbl\cf1\f51\fs18\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 12/31/13\cell\pard\plain\intbl\cf1\f51\fs18\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 12/31/14\cell\pard\plain\intbl\cf1\f51\fs18\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 12/31/15\cell\pard\plain\intbl\cf1\f51\fs18\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 12/31/16\cell\pard\plain\intbl\cf1\f51\fs18\b\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 12/31/17\cell\pard\plain\intbl\cf1\f51\fs18\b\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Idera Pharmaceuticals, Inc.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 100\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 520\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 496\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 347\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 169\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 237\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Russell 2000 Index\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 100\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 139\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 146\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 139\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 169\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 194\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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{\trowd\trqc\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2562\clbrdrt\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2802\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3164\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3704\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3969\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4331\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4871\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5136\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5498\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6038\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6303\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6665\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7205\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7470\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7832\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8372\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8637\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8999\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9539\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9682\trrh264
\pard\plain\intbl\cf1\f51\fs20\ql Nasdaq Biotechnology Index\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 100\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 166\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 223\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 249\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 196\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 239\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2562\clbrdrt\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2802\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3164\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3704\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3969\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4331\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4871\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5136\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5498\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6038\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6303\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6665\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7205\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7470\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7832\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8372\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8637\clbrdrl\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8999\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9539\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9682\trrh264\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 63\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\li1210\fi-1210\cf1\f51\fs2\ql \~{\*\bkmkstart item_1_3_8}{\*\bkmkend item_1_3_8}\par\pard\plain\li1210\fi-1210\cf11\f51\fs24\b\ql Item\~6.Selected Financial Data.{\*\bkmkstart item6selectedfinancialdata_37975}{\*\bkmkend item6selectedfinancialdata_37975}\par\pard\plain\li1210\fi-1210\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql The following selected financial data are derived from our financial statements. The data should be read in\plain\cf1\f51\fs20\ql conjunction with Management\u8217?s Discussion and Analysis of Financial Condition and Results of Operations\plain\cf1\f51\fs20\ql and the financial statements, related notes, and other financial information included elsewhere in this Annual Report\plain\cf1\f51\fs20\ql on Form 10-K.\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh66
\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh66\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9548\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Year Ended December\~31,\~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9548\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4490\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4755\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5754\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6019\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7018\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7283\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8282\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8547\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9546\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2015\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2014\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2013\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4490\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4755\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5754\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6019\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7018\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7283\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8282\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8547\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9546\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3491\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9548\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc (In\~thousands,\~except\~per\~share\~data)\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3491\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9548\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh446
\pard\plain\intbl\cf1\f51\fs18\b\ql Statement of Operations and\plain\intbl\cf1\f51\fs18\b\ql Comprehensive (Loss) Income Data:\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh446\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Alliance revenue\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 902\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 16,199\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 249\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 73\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 47\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Operating expenses:\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\li132\cf1\f51\fs18\ql Research and development\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 50,653\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 39,824\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 33,699\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 27,493\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 10,475\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\li132\cf1\f51\fs18\ql General and administrative\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 16,716\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 15,132\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 15,396\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 11,332\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 7,741\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\li396\cf1\f51\fs18\ql Total operating expenses\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 67,369\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 54,956\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 49,095\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 38,825\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 18,216\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Loss from operations\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (66,467)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,757)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (48,846)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,752)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (18,169)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Other income (expense):\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\li132\cf1\f51\fs18\ql Interest income\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 574\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 415\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 357\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 66\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 11\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\li132\cf1\f51\fs18\ql Interest expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (50)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (80)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (105)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (27)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\li132\cf1\f51\fs18\ql Foreign currency exchange gain (loss)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (41)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 33\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 39\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 71\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (68)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Net loss\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (65,984)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,389)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (48,555)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,642)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (18,226)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh668
\pard\plain\intbl\cf1\f51\fs18\ql Loss on extinguishment of convertible\plain\intbl\cf1\f51\fs18\ql preferred stock, and preferred stock\plain\intbl\cf1\f51\fs18\ql accretion and dividends\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 519\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 2,866\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh668\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh446
\pard\plain\intbl\cf1\f51\fs18\ql Net loss applicable to common\plain\intbl\cf1\f51\fs18\ql stockholders\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (65,984)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,389)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (48,555)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (39,161)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (21,092)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh446\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh445
\pard\plain\intbl\cf1\f51\fs18\ql Net loss per share applicable to common\plain\intbl\cf1\f51\fs18\ql stockholders - basic and diluted\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (0.42)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (0.30)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (0.42)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (0.47)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (0.48)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh445\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh891
\pard\plain\intbl\cf1\f51\fs18\ql Weighted-average number of common\plain\intbl\cf1\f51\fs18\ql shares used in computing net loss per\plain\intbl\cf1\f51\fs18\ql common share applicable to common\plain\intbl\cf1\f51\fs18\ql stockholders\~- basic and diluted (1)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 157,398\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 127,597\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 115,092\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 82,827\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 43,906\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh891\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Comprehensive loss:\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Net loss\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (65,984)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,389)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (48,555)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,642)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (18,226)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Other comprehensive income (loss):\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh445
\pard\plain\intbl\li132\cf1\f51\fs18\ql Unrealized income (loss) on\plain\intbl\li132\cf1\f51\fs18\ql available-for-sale securities\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 17\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 117\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (117)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (10)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (7)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh445\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh445
\pard\plain\intbl\li264\cf1\f51\fs18\ql Total other comprehensive income\plain\intbl\li264\cf1\f51\fs18\ql (loss)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 17\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 117\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (117)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (10)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (7)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh445\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Comprehensive loss\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (65,967)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,272)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (48,672)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (38,652)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\cf1\f51\fs18\qr (18,233)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3700\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4489\clvertalb\cellx4754\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4963\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5752\clvertalb\cellx6017\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6226\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7015\clvertalb\cellx7280\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7489\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8278\clvertalb\cellx8543\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8752\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\b\ql Balance Sheet Data:\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Cash, cash equivalents and investments\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 112,629\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 109,014\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 87,157\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 48,571\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 35,592\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Working capital\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 106,512\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 101,691\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 56,427\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 35,384\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 25,867\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Total assets\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 118,417\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 113,231\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 92,276\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 51,426\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 36,867\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Capital lease obligations\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 15\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 15\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 22\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 21\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~9\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Note payable\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 209\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 501\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 762\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 870\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Accumulated deficit\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (604,494)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (538,470)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (500,081)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (451,526)\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr (412,884)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3226\clvertalb\cellx3491\clvertalb\cellx3700\clvertalb\cellx4489\clvertalb\cellx4754\clvertalb\cellx4963\clvertalb\cellx5752\clvertalb\cellx6017\clvertalb\cellx6226\clvertalb\cellx7015\clvertalb\cellx7280\clvertalb\cellx7489\clvertalb\cellx8278\clvertalb\cellx8543\clvertalb\cellx8752\clvertalb\cellx9541\clvertalb\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs18\ql Total stockholders\u8217? equity\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 107,695\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 103,349\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 83,582\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 43,402\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 32,452\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3491\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3700\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4754\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4963\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6017\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7015\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7489\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8278\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8752\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9541\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\par\pard\plain
{\trowd\clvertalc\cellx1\cellx360\clvertalc\cellx361\cellx9688\trrh605
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs18\ql (1)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs18\ql Computed on the basis described in Note\~15 to the financial statements appearing elsewhere in this Annual Report on\plain\intbl\cf1\f51\fs18\ql Form\~10-K.\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\clvertalc\cellx1\cellx360\clvertalc\cellx361\cellx9688\trrh605\row}}}\pard\plain\li528\fi-528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 64\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}{\*\bkmkstart item_1_3_9}{\*\bkmkend item_1_3_9}\par\pard\plain\cf11\f51\fs24\b\ql Item 7. Management\u8217?s Discussion and Analysis of Financial Condition and Results\plain\cf11\f51\fs24\b\ql of Operations.{\*\bkmkstart item7managementsdiscussionandana}{\*\bkmkend item7managementsdiscussionandana}\par\pard\plain\sa264\cf1\f51\fs19\i\ql The following discussion and analysis of our financial condition and results of operations should be read in conjunction\plain\cf1\f51\fs19\i\ql with our audited financial statements and the related notes appearing elsewhere in this Annual Report on Form\~10-K.\par\pard\plain\cf12\f51\fs24\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Overview\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are a clinical-stage biopharmaceutical company focused on the discovery, development and\plain\cf1\f51\fs20\ql commercialization of novel oligonucleotide therapeutics for oncology and rare diseases. We use two distinct\plain\cf1\f51\fs20\ql proprietary drug discovery technology platforms to design and develop drug candidates: our Toll-like receptor, or\plain\cf1\f51\fs20\ql TLR, targeting technology and our nucleic acid chemistry technology (formerly referred to as our third generation\plain\cf1\f51\fs20\ql antisense, or 3GA, technology). We developed these platforms based on our scientific expertise and pioneering work\plain\cf1\f51\fs20\ql with synthetic oligonucleotides as therapeutic agents. Using our TLR targeting technology, we design synthetic\plain\cf1\f51\fs20\ql oligonucleotide-based drug candidates to modulate the activity of specific TLRs. In addition, using our nucleic acid\plain\cf1\f51\fs20\ql chemistry technology, we are developing drug candidates to turn off the messenger RNA, or mRNA, associated\plain\cf1\f51\fs20\ql with disease causing genes. We believe our nucleic acid chemistry technology may potentially reduce the\plain\cf1\f51\fs20\ql immunotoxicity and increase the potency of earlier generation antisense and RNA interference, or RNAi,\plain\cf1\f51\fs20\ql technologies.\par\pard\plain\fi528\cf1\f51\fs20\ql \~ \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our business strategy is focused on the clinical development of drug candidates for oncology and rare\plain\cf1\f51\fs20\ql diseases characterized by small, well-defined patient populations with serious unmet medical needs. We believe we\plain\cf1\f51\fs20\ql can develop and commercialize these targeted therapies on our own. To the extent we seek to develop drug\plain\cf1\f51\fs20\ql candidates for broader disease indications, we have entered into and may explore additional collaborative alliances\plain\cf1\f51\fs20\ql to support development and commercialization.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our TLR-targeted clinical-stage drug candidates are IMO-2125 and IMO-8400. IMO-2125 is an agonist of\plain\cf1\f51\fs20\ql TLR9, and IMO-8400 is an antagonist of TLR7, TLR8 and TLR9.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We are developing IMO-2125, via intra-tumoral injection, for the treatment of anti-PD1 refractory\plain\cf1\f51\fs20\ql metastatic melanoma in combination with ipilimumab, an anti-CTLA4 antibody marketed as Yervoy\u174? by\plain\cf1\f51\fs20\ql Bristol-Myers Squibb Company. We are also investigating the combination of intra-tumoral IMO-2125 in\plain\cf1\f51\fs20\ql combination with pembrolizumab for the treatment of anti-PD1 refractory metastatic melanoma and intratumoral\plain\cf1\f51\fs20\ql IMO-2125 in various solid tumors as monotherapy. We are developing IMO-8400 for the treatment of\plain\cf1\f51\fs20\ql dermatomyositis.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql At December\~31, 2017, we had an accumulated deficit of $604.5 million. We expect to incur substantial\plain\cf1\f51\fs20\ql operating losses in future periods. We do not expect to generate product revenue, sales-based milestones or\plain\cf1\f51\fs20\ql royalties from our development programs until we successfully complete development and obtain marketing\plain\cf1\f51\fs20\ql approval for drug candidates, either alone or in collaborations with third parties, which we expect will take a\plain\cf1\f51\fs20\ql number of years. In order to commercialize our drug candidates, we need to complete clinical development and\plain\cf1\f51\fs20\ql comply with comprehensive regulatory requirements.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Agreement and Plan of Merger\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As further described in Note 17\~to the financial statements appearing elsewhere in this Annual Report on\plain\cf1\f51\fs20\ql Form 10-K, on January 21, 2018, we entered into an Agreement and Plan of Merger, or the Merger Agreement,\plain\cf1\f51\fs20\ql with BioCryst Pharmaceuticals,\~Inc., a Delaware corporation, or BioCryst, Nautilus Holdco,\~Inc., a Delaware\plain\cf1\f51\fs20\ql corporation and a direct, wholly owned subsidiary of BioCryst, or Holdco,\~Island Merger Sub,\~Inc., a Delaware\plain\cf1\f51\fs20\ql corporation and a direct, wholly owned subsidiary of Holdco, or Merger Sub A, and Boat Merger Sub,\~Inc., a\plain\cf1\f51\fs20\ql Delaware corporation and a direct, wholly owned subsidiary of Holdco, or Merger Sub B.\~\~Pursuant to the Merger\plain\cf1\f51\fs20\ql Agreement, and subject to the satisfaction or waiver of the conditions specified therein, (a)\~Merger Sub A will be\plain\cf1\f51\fs20\ql merged with and into us, or the Idera Merger, with us surviving as a wholly owned subsidiary of Holdco, and\plain\cf1\f51\fs20\ql (b)\~Merger Sub B will be merged with and into BioCryst, or the BioCryst Merger, which we refer to together with\plain\cf1\f51\fs20\ql the Idera Merger as the Mergers, with BioCryst surviving as a wholly owned subsidiary of Holdco.\~Holdco will be\plain\cf1\f51\fs20\ql renamed prior to the closing of the Mergers.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 65\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\ql At the effective time of the Mergers, which we refer to as the Effective Time, (i)\~each share of our common\plain\cf1\f51\fs20\ql stock, par value $0.001 per share, issued and outstanding immediately prior to the Effective Time (other than the\plain\cf1\f51\fs20\ql shares that are owned by us, BioCryst, Holdco, Merger Sub A or Merger Sub B or any wholly owned subsidiary of\plain\cf1\f51\fs20\ql ours, BioCryst, Holdco, Merger Sub A or Merger Sub B) will be converted into the right to receive 0.20 of a newly\plain\cf1\f51\fs20\ql issued share of common stock, par value $0.01 per share, of Holdco and (ii)\~each share of our preferred stock, par\plain\cf1\f51\fs20\ql value $0.01 per share, issued and outstanding immediately prior to the Effective Time (other than the shares that are\plain\cf1\f51\fs20\ql owned by us, BioCryst, Holdco, Merger Sub A or Merger Sub B or any wholly owned subsidiary of ours, BioCryst,\plain\cf1\f51\fs20\ql Holdco, Merger Sub A or Merger Sub B) will be converted into the right to receive an amount of Holdco common\plain\cf1\f51\fs20\ql stock based on their liquidation preference.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi792\cf1\f51\fs20\ql We expect to consummate the Mergers in the second quarter of 2018. However, we have prepared this\plain\cf1\f51\fs20\ql Annual Report on Form 10-K and the forward-looking statements contained in this Annual Report on Form 10-K\plain\cf1\f51\fs20\ql as if we were going to remain an independent company. See Part I, Item 1A \u8220?Risk Factors\u8212?Risks\plain\cf1\f51\fs20\ql Relating to the Mergers\u8221? of this Annual Report on Form 10-K for certain risks related to the Mergers.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Critical Accounting Policies and Estimates\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql This management\u8217?s discussion and analysis of financial condition and results of operations is based on\plain\cf1\f51\fs20\ql our financial statements, which have been prepared in accordance with accounting principles generally accepted in\plain\cf1\f51\fs20\ql the United States. The preparation of these financial statements requires management to make estimates and\plain\cf1\f51\fs20\ql assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and\plain\cf1\f51\fs20\ql liabilities at the date of the financial statements and the reported amounts of revenues and expenses during the\plain\cf1\f51\fs20\ql reporting period. On an ongoing basis, management evaluates its estimates and judgments, including those related to\plain\cf1\f51\fs20\ql revenue recognition, stock-based compensation and research and development prepayments, accruals and related\plain\cf1\f51\fs20\ql expenses. Management bases its estimates and judgments on historical experience and on various other factors that\plain\cf1\f51\fs20\ql are believed to be reasonable under the circumstances, the results of which form the basis for making judgments\plain\cf1\f51\fs20\ql about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results\plain\cf1\f51\fs20\ql may differ from these estimates under different assumptions or conditions.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql We regard an accounting estimate or assumption underlying our financial statements as a \u8220?critical\plain\cf1\f51\fs20\ql accounting estimate\u8221? where:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh495\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql the impact of the estimates and assumptions on financial condition or operating performance is material.\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li1078\fi-396\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql While our significant accounting policies are described in more detail in Note 2 to our financial statements\plain\cf1\f51\fs20\ql appearing elsewhere in this Annual Report on Form 10-K, we believe the following accounting policies to be most\plain\cf1\f51\fs20\ql critical to the judgments and estimates used in the preparation of our financial statements.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Revenue Recognition\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql We recognize revenue in accordance with the Financial Accounting Standards Board\u8217?s, or FASB,\plain\cf1\f51\fs20\ql Accounting Standards Codification, or ASC, Topic 605,\plain\cf1\f51\fs20\i\ql Revenue Recognition\plain\cf1\f51\fs20\ql .\~\~Accordingly, revenue is recognized\plain\cf1\f51\fs20\ql for each unit of accounting when all of the following criteria are met:\par\pard\plain\cf1\f51\fs20\ql \~
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql delivery has occurred or services have been rendered;\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
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{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql collectability is reasonably assured.\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\fi616\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Amounts received prior to satisfying the revenue recognition criteria are recognized as deferred revenue in our\plain\cf1\f51\fs20\ql balance sheet.\~\~Amounts expected to be recognized as revenue within the 12 months following the balance\par\pard\plain\sb528\cf1\f51\fs20\qc 66\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql sheet date are classified as deferred revenue, current.\~\~Amounts not expected to be recognized as revenue within the\plain\cf1\f51\fs20\ql 12 months following the balance sheet date are classified as deferred revenue, net of current portion.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Our revenues have primarily been generated through collaborative research, development and/or\plain\cf1\f51\fs20\ql commercialization agreements.\~\~The terms of these agreements typically may include payment to us of one or more\plain\cf1\f51\fs20\ql of the following:\~\~nonrefundable, up-front license fees, research, development and commercial milestone payments,\plain\cf1\f51\fs20\ql other contingent payments due based on the activities of the counterparty or the reimbursement by licensees of costs\plain\cf1\f51\fs20\ql associated with patent maintenance.\~\~Each of these types of revenue are recorded as Alliance revenues in our\plain\cf1\f51\fs20\ql statement of operations.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql For each collaborative research, development and/or commercialization agreement, which results in revenues,\plain\cf1\f51\fs20\ql we determine (i) whether multiple deliverables exist, (ii) whether the delivered elements have value to the customer\plain\cf1\f51\fs20\ql on a stand-alone basis, (iii) how the deliverables should be separated or combined and (iv) how the consideration\plain\cf1\f51\fs20\ql should be allocated to the deliverables.\~\par\pard\plain\sb286\fi550\cf1\f51\fs20\ql Arrangement consideration that is fixed or determinable is allocated among the separate units of accounting\plain\cf1\f51\fs20\ql using the relative selling price method. Then, the applicable revenue recognition criteria in ASC 605 are applied to\plain\cf1\f51\fs20\ql each of the separate units of accounting in determining the appropriate period and pattern of recognition. We\plain\cf1\f51\fs20\ql determine the selling price of a unit of accounting following the hierarchy of evidence prescribed by ASC 605-25.\plain\cf1\f51\fs20\ql Accordingly, we determine the estimated selling price for units of accounting within each arrangement using\plain\cf1\f51\fs20\ql vendor-specific objective evidence, or VSOE, of selling price, if available, third-party evidence, or TPE, of selling\plain\cf1\f51\fs20\ql price if VSOE is not available, or best estimate of selling price, or BESP, if neither VSOE nor TPE is available.\plain\cf1\f51\fs20\ql We typically use BESP to estimate the selling price, since we generally do not have VSOE or TPE of selling price\plain\cf1\f51\fs20\ql for our units of accounting. Determining the BESP for a unit of accounting requires significant judgment. In\plain\cf1\f51\fs20\ql developing the BESP for a unit of accounting, we consider applicable market conditions and relevant entity-specific\plain\cf1\f51\fs20\ql factors, including factors that were contemplated in negotiating the agreement with the customer and estimated\plain\cf1\f51\fs20\ql costs. We validate the BESP for units of accounting by evaluating whether changes in the key assumptions used to\plain\cf1\f51\fs20\ql determine the BESP will have a significant effect on the allocation of arrangement consideration between multiple\plain\cf1\f51\fs20\ql units of accounting.\par\pard\plain\sb286\fi550\cf1\f51\fs20\ql Options are considered substantive if, at the inception of the arrangement, we are at risk as to whether the\plain\cf1\f51\fs20\ql collaborator will choose to exercise the option. Factors that we consider in evaluating whether an option is\plain\cf1\f51\fs20\ql substantive include the overall objective of the arrangement, the benefit the collaborator might obtain from the\plain\cf1\f51\fs20\ql arrangement without exercising the option, the cost to exercise the option and the likelihood that the option will be\plain\cf1\f51\fs20\ql exercised. For arrangements under which an option is considered substantive, we do not consider the item\plain\cf1\f51\fs20\ql underlying the option to be a deliverable at the inception of the arrangement and the associated option fees are not\plain\cf1\f51\fs20\ql included in allocable arrangement consideration, assuming the option is not priced at a significant and incremental\plain\cf1\f51\fs20\ql discount. Conversely, for arrangements under which an option is not considered substantive or if an option is priced\plain\cf1\f51\fs20\ql at a significant and incremental discount, we would consider the item underlying the option to be a deliverable at\plain\cf1\f51\fs20\ql the inception of the arrangement and a corresponding amount would be included in allocable arrangement\plain\cf1\f51\fs20\ql consideration. The license to the first product candidate is considered a deliverable at the inception of the\plain\cf1\f51\fs20\ql arrangement but options to license any additional product candidates are substantive options and therefore are not\plain\cf1\f51\fs20\ql considered deliverables at inception.\par\pard\plain\sb286\fi550\cf1\f51\fs20\ql We recognize arrangement consideration allocated to each unit of accounting when all of the revenue\plain\cf1\f51\fs20\ql recognition criteria in ASC 605 are satisfied for that particular unit of accounting. We will recognize as revenue\plain\cf1\f51\fs20\ql arrangement consideration attributed to licenses that have standalone value from the other deliverables to be\plain\cf1\f51\fs20\ql provided in an arrangement upon delivery. We will recognize as revenue arrangement consideration attributed to\plain\cf1\f51\fs20\ql licenses that do not have standalone value from the other deliverables to be provided in an arrangement over our\plain\cf1\f51\fs20\ql estimated performance period as the arrangement would be accounted for as a single unit of accounting.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi616\cf1\f51\fs20\ql Our multiple element revenue arrangements may include the following:\par\pard\plain\fi616\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\i\ql Up-front License Fees:\plain\cf1\f51\fs20\ql If a license does not have stand-alone value, we recognize revenues from\plain\cf1\f51\fs20\ql nonrefundable, up-front license fees on a straight-line basis over the contracted or estimated period of performance\plain\cf1\f51\fs20\ql of the services under the related agreement, unless evidence suggests that revenue is earned or obligations are\plain\cf1\f51\fs20\ql fulfilled in a different pattern. We evaluate the period of performance each reporting period and adjust the period of\plain\cf1\f51\fs20\ql performance on a prospective basis if there are changes to be made. If a license were to have\par\pard\plain\sb528\cf1\f51\fs20\qc 67\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql stand-alone value and the other criteria of revenue recognition were satisfied, then revenue would be recognized in\plain\cf1\f51\fs20\ql the period earned.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\i\ql Milestone Payments:\plain\cf1\f51\fs20\ql At the inception of an agreement that includes research and development milestone\plain\cf1\f51\fs20\ql payments, we evaluate whether each milestone is substantive or represents a deliverable of the counterparty to the\plain\cf1\f51\fs20\ql agreement. We recognize revenues related to substantive milestones in full in the period in which the substantive\plain\cf1\f51\fs20\ql milestone is achieved if payment is reasonably assured. If a milestone is a deliverable of the counterparty to the\plain\cf1\f51\fs20\ql agreement, it is considered contingent revenue and is recognized when we are informed by the counterparty that\plain\cf1\f51\fs20\ql they have achieved it and such amount is reasonably assured of payment.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\i\ql Research and Development Activities:\plain\cf1\f51\fs20\ql If we are entitled to reimbursement from our collaborators for specified\plain\cf1\f51\fs20\ql research and development activities or the reimbursement of costs associated with patent maintenance, we determine\plain\cf1\f51\fs20\ql whether such funding would result in alliance revenues or an offset to research and development expenses.\plain\cf1\f51\fs20\ql Reimbursement of patent maintenance costs are recognized during the period in which the related expenses are\plain\cf1\f51\fs20\ql incurred as alliance revenues in our statement of operations.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\i\ql Royalties\plain\cf1\f51\fs20\ql : If we are entitled to receive royalties from our collaborator for product sales, we will recognize\plain\cf1\f51\fs20\ql royalty revenue in the period of sale of the related product(s), based on the underlying contract terms, provided that\plain\cf1\f51\fs20\ql the reported sales are reliably measurable and we have no remaining performance obligations, assuming all other\plain\cf1\f51\fs20\ql revenue recognition criteria are met.\par\pard\plain\sb110\fi792\cf1\f51\fs20\ql Under the terms of our exclusive license and collaboration agreement with Vivelix Pharmaceuticals, Ltd.,\plain\cf1\f51\fs20\ql or Vivelix, we are eligible for future IMO-9200 related development, regulatory and sales milestone payments\plain\cf1\f51\fs20\ql totaling up to $140 million, including development and regulatory milestones totaling up to $65 million and sales\plain\cf1\f51\fs20\ql milestones totaling up to $75 million, and escalating royalties ranging from the mid single-digits to low\plain\cf1\f51\fs20\ql double-digits of global net sales, which percentages are subject to reduction under agreed upon circumstances. As it\plain\cf1\f51\fs20\ql relates to back-up compounds we are eligible for related designation payments and development, regulatory sales\plain\cf1\f51\fs20\ql and milestone payments totaling up to $52.5 million, including development and regulatory milestones totaling up to\plain\cf1\f51\fs20\ql $35 million and sales milestones totaling up to $17.5 million and escalating royalties ranging from the mid\plain\cf1\f51\fs20\ql single-digits to low double-digits of global net sales, which percentages are subject to reduction under agreed upon\plain\sa110\cf1\f51\fs20\ql circumstances.\~\par\pard\plain\fi550\cf1\f51\fs20\ql Under the terms of our collaboration and license agreement with GlaxoSmithKline Intellectual Property\plain\cf1\f51\fs20\ql Development Limited, or GSK, we are eligible to receive a total of up to approximately $20 million in upfront,\plain\cf1\f51\fs20\ql license, research, clinical development and commercialization milestone payments, including the $2.5 million\plain\cf1\f51\fs20\ql upfront, non-refundable, non-creditable cash payment received upon execution of the agreement. Of the\plain\cf1\f51\fs20\ql approximately $20 million in total payments we are eligible to receive, $1 million is payable by GSK upon the\plain\cf1\f51\fs20\ql designation of a development candidate from the initial target and $17 million is payable by GSK upon the\plain\cf1\f51\fs20\ql achievement of clinical milestones and commercial milestones. In addition, we are eligible to receive royalty\plain\cf1\f51\fs20\ql payments based on net sales of licensed products following commercialization at varying rates of up to five percent\plain\cf1\f51\fs20\ql on annual net sales.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql We are adopting new revenue accounting guidance{\*\bkmkstart _cp_text_1_588_12112272}{\*\bkmkend _cp_text_1_588_12112272}\plain\cf1\f51\fs20\ql in the first quarter of 2018. With respect to both our\plain\cf1\f51\fs20\ql license and collaboration agreements with Vivelix and GSK, we are substantially complete with our assessment and\plain\cf1\f51\fs20\ql currently estimate that there will be no material impact to the amount of revenue previously recognized in our\plain\cf1\f51\fs20\ql historical financial statements after adoption of the new guidance.\~For further discussion, see Note 2,\plain\cf1\f51\fs20\ql \u8220?Summary of Significant Accounting Policies{\*\bkmkstart _cp_text_1_593_12112272}{\*\bkmkend _cp_text_1_593_12112272}\plain\cf1\f51\fs20\ql \u8212?New Accounting Pronouncements\u8212?Recently\plain\cf1\f51\fs20\ql Issued (Not Yet Adopted) Accounting Pronouncements\u8221?, in the Notes to Financial Statements included\plain\cf1\f51\fs20\ql elsewhere in this Annual Report on Form 10-K{\*\bkmkstart _cp_text_1_594_12112272}{\*\bkmkend _cp_text_1_594_12112272}\plain\cf1\f51\fs20\ql for further discussion regarding Topic 606.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Stock-Based Compensation\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql We recognize all share-based payments to employees and directors as expense in our statements of operations\plain\cf1\f51\fs20\ql and comprehensive loss based on their fair values. We record compensation expense over an award\u8217?s\plain\cf1\f51\fs20\ql requisite service period, or vesting period, based on the award\u8217?s fair value at the date of grant. Our policy is\plain\cf1\f51\fs20\ql to charge the fair value of stock options as an expense, adjusted for forfeitures, on a straight-line basis over the\plain\cf1\f51\fs20\ql vesting period, which is generally four years for employees and one year for directors.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 68\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi550\cf1\f51\fs20\ql We use the Black-Scholes option pricing model to estimate the fair value of stock option grants. The\plain\cf1\f51\fs20\ql Black-Scholes option pricing model relies on a number of key assumptions to calculate estimated fair values,\plain\cf1\f51\fs20\ql including assumptions as to average risk-free interest rate, expected dividend yield, expected life and expected\plain\cf1\f51\fs20\ql volatility. For the assumed risk-free interest rate, we use the U.S.\~Treasury security rate with a term equal to the\plain\cf1\f51\fs20\ql expected life of the option. Our assumed dividend yield of zero is based on the fact that we have never paid cash\plain\cf1\f51\fs20\ql dividends to common stockholders and have no present intention to pay cash dividends. We use an expected option\plain\cf1\f51\fs20\ql life based on actual experience. Our assumption for expected volatility is based on the actual stock-price volatility\plain\cf1\f51\fs20\ql over a period equal to the expected life of the option.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql If factors change and we employ different assumptions for estimating stock-based compensation expense in\plain\cf1\f51\fs20\ql future periods, or if we decide to use a different valuation model, the stock-based compensation expense we\plain\cf1\f51\fs20\ql recognize in future periods may differ significantly from what we have recorded in the current period and could\plain\cf1\f51\fs20\ql materially affect our operating income (loss), net income (loss) and earnings (loss) per share. It may also result in a\plain\cf1\f51\fs20\ql lack of comparability with other companies that use different models, methods and assumptions. The Black-Scholes\plain\cf1\f51\fs20\ql option pricing model was developed for use in estimating the fair value of traded options that have no vesting\plain\cf1\f51\fs20\ql restrictions and are fully transferable. These characteristics are not present in our option grants. Although the\plain\cf1\f51\fs20\ql Black-Scholes option pricing model is widely used, existing valuation models, including the Black-Scholes option\plain\cf1\f51\fs20\ql pricing model, may not provide reliable measures of the fair values of our stock-based compensation.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Research and Development Prepayments, Accruals and Related Expenses\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql As part of the process of preparing our financial statements, we are required to estimate our accrued and\plain\cf1\f51\fs20\ql prepaid expenses for research and development activities performed by third parties, including Clinical Research\plain\cf1\f51\fs20\ql Organizations, or CROs, and clinical investigators. These estimates are made as of the reporting date of the work\plain\cf1\f51\fs20\ql completed over the life of the individual study in accordance with agreements established with CROs and clinical\plain\cf1\f51\fs20\ql trial sites. Some CROs invoice us on a monthly basis, while others invoice upon achievement of milestones and the\plain\cf1\f51\fs20\ql expense is recorded as services are rendered. We determine the estimates of research and development activities\plain\cf1\f51\fs20\ql incurred at the end of each reporting period through discussion with internal personnel and outside service providers\plain\cf1\f51\fs20\ql as to the progress or stage of completion of trials or services, as of the end of each reporting period, pursuant to\plain\cf1\f51\fs20\ql contracts with clinical trial centers and CROs and the agreed upon fee to be paid for such services. We periodically\plain\cf1\f51\fs20\ql confirm the accuracy of our estimates with the service providers and make adjustments if necessary. Clinical trial\plain\cf1\f51\fs20\ql site costs related to patient enrollments are recorded as patients are entered into the trial.\par\pard\plain\sb528\cf1\f51\fs20\qc 69\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\ql Results of Operations\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf11\f51\fs24\b\i\ql Years ended December\~31, 2017, 2016 and 2015\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Alliance Revenue\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Alliance revenue for the years ended December 31, 2017, 2016 and 2015 were comprised of the following:\~\par\pard\plain\fi550\cf1\f51\fs20\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs18\ql GSK collaboration\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 863\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 1,111\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 126\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -22%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 782%\cell\pard\plain\intbl\cf1\f51\fs18\qc (2)\cell{
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\pard\plain\intbl\cf1\f51\fs18\ql Other\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 25\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 88\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 123\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -72%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -28%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3209\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3401\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3601\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4369\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4609\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4809\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5581\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5821\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6021\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6795\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7035\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8093\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8333\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9390\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223\row}}}
{\trowd\clvertalb\cellx3209\clvertalb\cellx3401\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3601\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4369\clvertalb\cellx4609\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4809\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5581\clvertalb\cellx5821\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6021\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6795\clvertalb\cellx7035\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8093\clvertalb\cellx8333\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9390\clvertalb\cellx9688\trrh223
\pard\plain\intbl\li264\cf1\f51\fs18\ql Total Alliance Revenue\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 902\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 16,199\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 249\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -94%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 6406%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\clvertalb\cellx3209\clvertalb\cellx3401\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3601\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4369\clvertalb\cellx4609\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4809\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5581\clvertalb\cellx5821\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6021\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6795\clvertalb\cellx7035\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8093\clvertalb\cellx8333\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9390\clvertalb\cellx9688\trrh223\row}}}
{\trowd\clvertalb\cellx3209\clvertalb\cellx3401\clvertalb\cellx3601\clvertalb\cellx4369\clvertalb\cellx4609\clvertalb\cellx4809\clvertalb\cellx5581\clvertalb\cellx5821\clvertalb\cellx6021\clvertalb\cellx6795\clvertalb\cellx7035\clvertalb\cellx8093\clvertalb\cellx8333\clvertalb\cellx9390\clvertalb\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\clvertalb\cellx3209\clvertalb\cellx3401\clvertalb\cellx3601\clvertalb\cellx4369\clvertalb\cellx4609\clvertalb\cellx4809\clvertalb\cellx5581\clvertalb\cellx5821\clvertalb\cellx6021\clvertalb\cellx6795\clvertalb\cellx7035\clvertalb\cellx8093\clvertalb\cellx8333\clvertalb\cellx9390\clvertalb\cellx9688\trrh248\row}}}\pard\plain\fi550\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx1\cellx324\clvertalc\cellx325\cellx9688\trrh2002
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (1)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Vivelix collaboration revenues for the year ended December 31, 2016 reflects the recognition of\plain\intbl\cf1\f51\fs20\ql an upfront, non-refundable fee of $15 million received in connection with the execution of the\plain\intbl\cf1\f51\fs20\ql Vivelix Agreement in November 2016. Vivelix collaboration revenues for the year ended\plain\intbl\cf1\f51\fs20\ql December 31, 2017 reflects reimbursement of certain research activities we have performed\plain\intbl\cf1\f51\fs20\ql under the Vivelix Agreement.\~\~See Part I, Item 1, "Business \u8212?Collaborative Alliances" of\plain\intbl\cf1\f51\fs20\ql this Form 10-K for additional details regarding our collaboration with Vivelix and Note 8 to\plain\intbl\cf1\f51\fs20\ql the financial statements appearing elsewhere in this Annual Report on Form 10-K for\plain\intbl\cf1\f51\fs20\ql information on the related accounting treatment.\cell{
{\trowd\clvertalc\cellx1\cellx324\clvertalc\cellx325\cellx9688\trrh2002\row}}}\pard\plain\li946\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx1\cellx324\clvertalc\cellx325\cellx9688\trrh2970
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (2)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql GSK collaboration revenues for the years ended December 31, 2017 and 2016 primarily relate\plain\intbl\cf1\f51\fs20\ql to the recognition of a $2.5 million upfront payment received in connection with the execution\plain\intbl\cf1\f51\fs20\ql of the GSK Agreement in November 2015, which was initially recorded as deferred\plain\intbl\cf1\f51\fs20\ql revenue.\~\~We are recognizing this deferred revenue as revenue on a straight line basis over the\plain\intbl\cf1\f51\fs20\ql anticipated performance period under the GSK Agreement. The decrease in GSK collaboration\plain\intbl\cf1\f51\fs20\ql revenues during 2017 as compared to 2016 is primarily due to a change that we made during\plain\intbl\cf1\f51\fs20\ql the second quarter of 2017 with respect to our anticipated performance period under our\plain\intbl\cf1\f51\fs20\ql collaboration with GSK from the original estimate of 27 months to an updated estimate of 36\plain\intbl\cf1\f51\fs20\ql months, which we accounted for on a prospective basis. See Part I, Item 1, "Business\plain\intbl\cf1\f51\fs20\ql \u8212?Collaborative Alliances" of this Form 10-K for additional details regarding our\plain\intbl\cf1\f51\fs20\ql collaboration with GSK and Note 8 to the financial statements appearing elsewhere in this\plain\intbl\cf1\f51\fs20\ql Annual Report on Form 10-K for information on the related accounting treatment.\cell{
{\trowd\clvertalc\cellx1\cellx324\clvertalc\cellx325\cellx9688\trrh2970\row}}}\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Research and Development Expenses\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql For each of our research and development programs, we incur both direct and indirect expenses. We track\plain\cf1\f51\fs20\ql direct research and development expenses by program, which include third party costs such as contract research,\plain\cf1\f51\fs20\ql consulting and clinical trial and manufacturing costs. We do not allocate indirect research and development\plain\cf1\f51\fs20\ql expenses, which may include regulatory, laboratory (equipment and supplies), personnel, facility and other overhead\plain\cf1\f51\fs20\ql costs (including depreciation and amortization), to specific programs.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 70\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi594\cf1\f51\fs20\ql In the table below, research and development expenses are set forth in the following categories which are\plain\cf1\f51\fs20\ql discussed beneath the table:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh66\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3804\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4566\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4806\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5006\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5776\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6016\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6216\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6986\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8186\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8431\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9391\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\qc \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3804\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4566\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4806\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5006\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5776\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6016\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6216\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6986\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8186\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8431\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9391\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6987\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7227\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8187\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8432\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9392\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Year Ended December\~31,\~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6987\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7227\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8187\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8432\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9392\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6987\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7227\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9392\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc (in thousands)\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc % Change\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6987\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7227\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9392\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4566\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4806\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5776\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6016\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6986\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8186\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8431\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9391\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2015\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2017 vs 2016\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2016 vs 2015\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3474\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3604\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4566\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4806\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5776\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6016\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6986\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7226\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8186\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8431\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9391\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql IMO-2125 external development expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 10,930\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 4,187\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 1,183\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 161%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 254%\cell\pard\plain\intbl\cf1\f51\fs18\qc (1)\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql IMO-8400 external development expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 8,484\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 11,150\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 9,561\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -24%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 17%\cell\pard\plain\intbl\cf1\f51\fs18\qc (2)\cell{
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql IMO-9200 external development expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~7\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 392\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 2,498\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -98%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -84%\cell\pard\plain\intbl\cf1\f51\fs18\qc (3)\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql Other drug development expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 16,675\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 14,221\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 11,847\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 17%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 20%\cell\pard\plain\intbl\cf1\f51\fs18\qc (4)\cell{
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql Basic discovery expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 8,980\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 9,874\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 8,610\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr -9%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 15%\cell\pard\plain\intbl\cf1\f51\fs18\qc (5)\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3804\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4566\clvertalb\cellx4806\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5006\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5776\clvertalb\cellx6016\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6216\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6986\clvertalb\cellx7226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8186\clvertalb\cellx8431\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9391\clvertalb\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql Severance and option modification expense\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 5,577\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\qr \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 100%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 0%\cell\pard\plain\intbl\cf1\f51\fs18\qc (6)\cell{
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3804\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4566\clvertalb\cellx4806\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5006\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5776\clvertalb\cellx6016\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6216\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6986\clvertalb\cellx7226\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8186\clvertalb\cellx8431\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9391\clvertalb\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223
\pard\plain\intbl\li264\cf1\f51\fs18\ql Total research and development expenses\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 50,653\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 39,824\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 33,699\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 27%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs18\qr 18%\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3474\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3604\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3804\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4806\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5006\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5776\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6016\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6216\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6986\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7226\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8186\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8431\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9391\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh223\row}}}
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh223
\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell{
{\trowd\trqc\clvertalb\cellx3474\clvertalb\cellx3604\clvertalb\cellx3804\clvertalb\cellx4566\clvertalb\cellx4806\clvertalb\cellx5006\clvertalb\cellx5776\clvertalb\cellx6016\clvertalb\cellx6216\clvertalb\cellx6986\clvertalb\cellx7226\clvertalb\cellx8186\clvertalb\cellx8431\clvertalb\cellx9391\clvertalb\cellx9688\trrh223\row}}}\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh4230
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (1)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\i\ql IMO-2125 External Development Expenses.\plain\intbl\cf1\f51\fs20\ql \~\~\~\~These expenses include external expenses that we have\plain\intbl\cf1\f51\fs20\ql incurred in connection with the development of IMO-2125 as part of our immuno-oncology program.\plain\intbl\cf1\f51\fs20\ql These external expenses include payments to independent contractors and vendors for drug development\plain\intbl\cf1\f51\fs20\ql activities conducted after the initiation of IMO-2125 clinical development in immuno-oncology, but\plain\intbl\cf1\f51\fs20\ql exclude internal costs such as payroll and overhead expenses. We commenced clinical development of\plain\intbl\cf1\f51\fs20\ql IMO-2125 as part of our immuno-oncology program in July 2015 and from July 2015 through December\plain\intbl\cf1\f51\fs20\ql 31, 2017 we incurred approximately $16.3 million in IMO-2125 external development expenses as part of\plain\intbl\cf1\f51\fs20\ql our immuno-oncology program, including costs associated with the preparation for and conduct of the\plain\intbl\cf1\f51\fs20\ql ongoing Phase 1/2 clinical trial to assess the safety and efficacy of IMO-2125 in combination with\plain\intbl\cf1\f51\fs20\ql ipilimumab and with pembrolizumab in patients with metastatic melanoma (Illuminate 204), the\plain\intbl\cf1\f51\fs20\ql preparation and conduct of our Phase 1b clinical trial of IMO-2125 monotherapy in patients with\plain\intbl\cf1\f51\fs20\ql refractory solid tumors (Illuminate 101), the preparation for our Phase 3 clinical trial of IMO-2125 in\plain\intbl\cf1\f51\fs20\ql combination with ipilimumab in patients with metastatic melanoma (Illuminate 301), and the manufacture\plain\intbl\cf1\f51\fs20\ql of additional drug substance for use in our clinical trials and additional nonclinical studies. The $16.3\plain\intbl\cf1\f51\fs20\ql million in IMO-2125 external development expenses excludes costs incurred prior to July 2015 with\plain\intbl\cf1\f51\fs20\ql respect to IMO-2125, including costs incurred for the development of IMO-2125 for the treatment of\plain\intbl\cf1\f51\fs20\ql patients with chronic hepatitis C virus which we discontinued in the third quarter of 2011.\cell{
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh4230\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The increases in our IMO-2125 external development expenses in both 2017 and 2016, as compared to\plain\li946\cf1\f51\fs20\ql the corresponding prior period, were primarily due to increases in costs associated with the design and\plain\li946\cf1\f51\fs20\ql planning for additional clinical trials of IMO-2125 and increased clinical activity under our ongoing\plain\li946\cf1\f51\fs20\ql Phase 1/2 clinical trial, including costs incurred with contract research organizations and drug\plain\li946\cf1\f51\fs20\ql manufacturing costs. In addition, expenses incurred during the 2017 period included costs associated with\plain\li946\cf1\f51\fs20\ql our Phase 1b clinical trial of IMO-2125 monotherapy in patients with refractory solid tumors, which was\plain\li946\cf1\f51\fs20\ql initiated in March 2017, and costs associated with the design and planning of our Phase 3 clinical trial of\plain\li946\cf1\f51\fs20\ql IMO-2125 in combination with ipilimumab in patients with metastatic melanoma, which was initiated in\plain\li946\cf1\f51\fs20\ql the first quarter of 2018.\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh3465
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (2)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\i\ql IMO-8400 External Development Expenses.\plain\intbl\cf1\f51\fs20\ql \~\~\~\~These expenses include external expenses that we have\plain\intbl\cf1\f51\fs20\ql incurred in connection with IMO-8400 since October 2012, when we commenced clinical development of\plain\intbl\cf1\f51\fs20\ql IMO-8400. These external expenses include payments to independent contractors and vendors for drug\plain\intbl\cf1\f51\fs20\ql development activities conducted after the initiation of IMO-8400 clinical development but exclude\plain\intbl\cf1\f51\fs20\ql internal costs such as payroll and overhead expenses. Since October 2012, we have incurred\plain\intbl\cf1\f51\fs20\ql approximately $42.8 million in IMO-8400 external development expenses through December\~31, 2017,\plain\intbl\cf1\f51\fs20\ql including costs associated with our Phase 1 clinical trial in healthy subjects; our Phase 2 clinical trial in\plain\intbl\cf1\f51\fs20\ql patients with psoriasis, our Phase 1/2 clinical trial in patients with Waldenstr\u246?m\u8217?s\plain\intbl\cf1\f51\fs20\ql macroglobulinemia and our Phase 1/2 clinical trial in patients with diffuse large B-cell lymphoma, or\plain\intbl\cf1\f51\fs20\ql DLBCL, harboring the MYD88 L265P oncogenic mutation, which we discontinued in September 2016;\plain\intbl\cf1\f51\fs20\ql the preparation for and conduct of our ongoing Phase 2 clinical trial in patients with dermatomyositis; the\plain\intbl\cf1\f51\fs20\ql manufacture of additional drug substance for use in our clinical trials; and expenses associated with our\plain\intbl\cf1\f51\fs20\ql collaboration with Abbott Molecular for the development of a companion diagnostic for identification of\plain\intbl\cf1\f51\fs20\ql patients with DLBCL harboring the MYD88 L265P oncogenic mutation.\cell{
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh3465\row}}}\pard\plain\sb528\cf1\f51\fs20\qc 71\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The decrease in our IMO-8400 external development expenses in 2017, as compared to 2016, was\plain\li946\cf1\f51\fs20\ql primarily{\*\bkmkstart _cp_text_1_628_12112272}{\*\bkmkend _cp_text_1_628_12112272}\plain\li946\cf1\f51\fs20\ql due to lower costs incurred on clinical development of IMO-8400 for B-cell lymphomas,\plain\li946\cf1\f51\fs20\ql including our trials in Waldenstr\u246?m\u8217?s macroglobulinemia and DLBCL{\*\bkmkstart _cp_text_1_630_12112272}{\*\bkmkend _cp_text_1_630_12112272}\plain\li946\cf1\f51\fs20\ql harboring the MYD88\plain\li946\cf1\f51\fs20\ql L265P oncogenic mutation{\*\bkmkstart _cp_text_4_631_12112272}{\*\bkmkend _cp_text_4_631_12112272}\plain\li946\cf1\f51\fs20\ql which we{\*\bkmkstart _cp_text_1_632_12112272}{\*\bkmkend _cp_text_1_632_12112272}\plain\li946\cf1\f51\fs20\ql discontinued in 2016, partially{\*\bkmkstart _cp_text_1_634_12112272}{\*\bkmkend _cp_text_1_634_12112272}\plain\li946\cf1\f51\fs20\ql offset by increased spending on our\plain\li946\cf1\f51\fs20\ql ongoing Phase 2 clinical trial of IMO-8400 in patients with dermatomyositis.\par\pard\plain\li946\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The increase in our IMO-8400 external development expenses in 2016, as compared to 2015, was\plain\li946\cf1\f51\fs20\ql primarily due to increases in costs associated with our ongoing Phase 2 clinical trial in patients with\plain\li946\cf1\f51\fs20\ql dermatomyositis and costs incurred in connection with the manufacture of additional drug substance for\plain\li946\cf1\f51\fs20\ql use in our clinical trials in 2016. An increase in the cost of conducting our Phase 1/2 clinical trial in\plain\li946\cf1\f51\fs20\ql patients with DLBCL harboring the MYD88 L265P oncogenic mutation also contributed to the increase\plain\li946\cf1\f51\fs20\ql in IMO-8400 external development expenses in 2016. These increases were partially offset by a decrease\plain\li946\cf1\f51\fs20\ql related to lower enrollment in our Phase 1/2 clinical trial in patients with Waldenstr\u246?m\u8217?s\plain\li946\cf1\f51\fs20\ql macroglobulinemia and a decrease in the cost of developing a companion diagnostic for identification of\plain\li946\cf1\f51\fs20\ql patients with B-cell lymphoma harboring the MYD88 L265P oncogenic mutation as compared to 2015.\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh2970
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (3)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\i\ql IMO-9200 External Development Expenses.\plain\intbl\cf1\f51\fs20\ql \~\~\~\~These expenses include external expenses that\plain\intbl\cf1\f51\fs20\ql we have incurred in connection with IMO-9200 since October 2014, when we commenced\plain\intbl\cf1\f51\fs20\ql clinical development of IMO-9200. These external expenses include payments to independent\plain\intbl\cf1\f51\fs20\ql contractors and vendors for drug development activities conducted after the initiation of\plain\intbl\cf1\f51\fs20\ql IMO-9200 clinical development but exclude internal costs such as payroll and overhead\plain\intbl\cf1\f51\fs20\ql expenses. We have incurred approximately $4.6 million in IMO-9200 external development\plain\intbl\cf1\f51\fs20\ql expenses from October 2014 through December 31, 2017 including costs associated with our\plain\intbl\cf1\f51\fs20\ql Phase 1 clinical trial in healthy subjects, the manufacture of additional drug substance for use\plain\intbl\cf1\f51\fs20\ql in our clinical and nonclinical trials and additional nonclinical studies. In September 2016, we\plain\intbl\cf1\f51\fs20\ql determined not to proceed with the development of IMO-9200 and, in November 2016, we\plain\intbl\cf1\f51\fs20\ql entered into the Vivelix Agreement, granting Vivelix worldwide rights to develop and market\plain\intbl\cf1\f51\fs20\ql IMO-9200 for nonmalignant gastrointestinal disorders.\cell{
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh2970\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The decreases in our IMO-9200 external development expenses in both 2017 and 2016, as compared to\plain\li946\cf1\f51\fs20\ql the corresponding prior period, primarily reflects lower spending on manufacturing and nonclinical\plain\li946\cf1\f51\fs20\ql toxicology as a result of our decision to not proceed with the development of IMO-9200 in September\plain\li946\cf1\f51\fs20\ql 2016. Accordingly, we anticipate our IMO-9200 external development expenses will be nominal going\plain\li946\cf1\f51\fs20\ql forward.\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh2002
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (4)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\i\ql Other Drug Development Expenses.\plain\intbl\cf1\f51\fs20\ql \~\~\~\~These expenses include external expenses associated with\plain\intbl\cf1\f51\fs20\ql preclinical development of identified compounds in anticipation of advancing these compounds into\plain\intbl\cf1\f51\fs20\ql clinical development, including IDRA-008. In addition, these expenses include internal costs, such as\plain\intbl\cf1\f51\fs20\ql payroll and overhead expenses, associated with preclinical development and products in clinical\plain\intbl\cf1\f51\fs20\ql development. The external expenses associated with preclinical compounds include payments to contract\plain\intbl\cf1\f51\fs20\ql vendors for manufacturing and the related stability studies, preclinical studies, including animal toxicology\plain\intbl\cf1\f51\fs20\ql and pharmacology studies, and professional fees. Other drug development expenses also include costs\plain\intbl\cf1\f51\fs20\ql associated with compounds that were previously being developed but are not currently being developed.\cell{
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh2002\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The increase in other drug development expenses in 2017, as compared to 2016, was primarily due to an\plain\li946\cf1\f51\fs20\ql increase in external costs of preclinical programs, including toxicology/pharmacology and bioanalytical\plain\li946\cf1\f51\fs20\ql studies, storage fees and awareness and education programs, in addition to higher payroll and overhead\plain\li946\cf1\f51\fs20\ql costs.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The increase in other drug development expenses in 2016, as compared to 2015, was primarily due the\plain\li946\cf1\f51\fs20\ql costs of additional headcount associated with our expanded drug development programs and costs\plain\li946\cf1\f51\fs20\ql associated with the manufacture of drug supplies for use in our nucleic acid chemistry research programs,\plain\li946\cf1\f51\fs20\ql partially offset by lower consulting costs during 2016. In addition, other drug development expenses in\plain\li946\cf1\f51\fs20\ql 2015 included costs associated with the manufacture of IMO-2055 drug supply and other drug\plain\li946\cf1\f51\fs20\ql development expenses of IMO-2125 incurred prior to the commencement of its clinical development in\plain\li946\cf1\f51\fs20\ql our immuno-oncology program in July 2015. Costs associated with the clinical development of\plain\li946\cf1\f51\fs20\ql IMO-2125 since July 2015 are included in IMO-2125 external development expenses.\par\pard\plain\sb528\cf1\f51\fs20\qc 72\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh1238
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (5)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\i\ql Basic Discovery Expenses.\plain\intbl\cf1\f51\fs20\ql \~\~\~\~These expenses include our internal and external expenses relating to our\plain\intbl\cf1\f51\fs20\ql discovery efforts with respect to our TLR-targeted programs, including agonists and antagonists of TLR3,\plain\intbl\cf1\f51\fs20\ql TLR7, TLR8 and TLR9, and our nucleic acid chemistry research programs. These expenses reflect\plain\intbl\cf1\f51\fs20\ql charges for laboratory supplies, external research, and professional fees, as well as payroll and overhead\plain\intbl\cf1\f51\fs20\ql expenses.\~\cell{
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh1238\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The decrease in basic discovery expenses in 2017, as compared to 2016, is primarily due to lower\plain\li946\cf1\f51\fs20\ql compensation related expenses, including salaries and non-cash stock-based compensation resulting from\plain\li946\cf1\f51\fs20\ql the resignation of our President of Research in May 2017 (see discussion of Severance and Option\plain\li946\cf1\f51\fs20\ql Modification Expenses below) as well as lower facility related charges, including overhead expenses.\par\pard\plain\li946\cf1\f51\fs20\ql \~\par\pard\plain\li946\cf1\f51\fs20\ql The increase in basic discovery expenses in 2016, as compared to 2015, was primarily due to increases in\plain\li946\cf1\f51\fs20\ql payroll and stock-based compensation associated with additional research and development headcount,\plain\li946\cf1\f51\fs20\ql the costs of laboratory supplies and facilities expenses during 2016. The increase in basic discovery\plain\li946\cf1\f51\fs20\ql expenses in 2016 was partially offset by decreases in external research and recruiting expenses in 2016.\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh1732
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql (6)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\i\ql Severance and Option Modification Expenses.\plain\intbl\cf1\f51\fs20\ql The expenses incurred during 2017 relate to charges for\plain\intbl\cf1\f51\fs20\ql severance benefits provided pursuant to a separation agreement entered into in April 2017 in connection\plain\intbl\cf1\f51\fs20\ql with the resignation of our former President of Research, effective May 31, 2017. Of the $5.6 million\plain\intbl\cf1\f51\fs20\ql incurred, $1.3 million relates to severance pay in the form of salary continuation payments which will be\plain\intbl\cf1\f51\fs20\ql paid over a two-year period through May 31, 2019 and a pro-rated 2017 bonus payment, and $4.3\plain\intbl\cf1\f51\fs20\ql million relates to non-cash stock-based compensation expense resulting from modifications to previously\plain\intbl\cf1\f51\fs20\ql issued stock option awards. No such expenses were incurred in 2016 or 2015.\cell{
{\trowd\clvertalc\cellx420\cellx840\clvertalc\cellx841\cellx9688\trrh1732\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We do not know if we will be successful in developing any drug candidate from our research and\plain\cf1\f51\fs20\ql development programs. At this time, and without knowing the results from our ongoing clinical trials of IMO-2125,\plain\cf1\f51\fs20\ql our ongoing clinical trial of IMO-8400, and our ongoing development of compounds in our nucleic acid chemistry\plain\cf1\f51\fs20\ql research program, we cannot reasonably estimate or know the nature, timing, and costs of the efforts that will be\plain\cf1\f51\fs20\ql necessary to complete the remainder of the development of, or the period, if any, in which material net cash inflows\plain\cf1\f51\fs20\ql may commence from, any drug candidate from our research and development programs. Moreover, the clinical\plain\cf1\f51\fs20\ql development of any drug candidate from our research and development programs is subject to numerous risks and\plain\cf1\f51\fs20\ql uncertainties associated with the duration and cost of clinical trials, which vary significantly over the life of a\plain\cf1\f51\fs20\ql project as a result of unanticipated events arising during clinical development.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql General and Administrative Expenses\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql General and administrative expenses consist primarily of payroll, stock-based compensation expense,\plain\cf1\f51\fs20\ql consulting fees and professional legal fees associated with our patent applications and maintenance, our corporate\plain\cf1\f51\fs20\ql regulatory filing requirements, our corporate legal matters, and our business development initiatives. For the years\plain\cf1\f51\fs20\ql ended December 31, 2017, 2016 and 2015, general and administrative expenses totaled $16.7 million, $15.1 million\plain\cf1\f51\fs20\ql and $15.4 million, respectively.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql General and administrative expenses increased by approximately $1.6 million, or 10.5%, in 2017, as\plain\cf1\f51\fs20\ql compared to 2016, primarily due to increases in corporate legal fees, investor relations and information technology\plain\cf1\f51\fs20\ql expenses.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql General and administrative expenses decreased by approximately $0.3 million, or 2%, in 2016, as compared\plain\cf1\f51\fs20\ql to 2015, primarily due to decreases in corporate legal fees and investor relations expenses, partially offset by\plain\cf1\f51\fs20\ql increases in payroll, stock compensation, legal fees associated with our patent filing and maintenance{\*\bkmkstart _cp_text_1_207_12112272}{\*\bkmkend _cp_text_1_207_12112272}\plain\cf1\f51\fs20\ql , and\plain\cf1\f51\fs20\ql accounting and auditing fees, including the cost of Sarbanes-Oxley compliance and the related internal control\plain\cf1\f51\fs20\ql audit.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 73\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\b\i\ql Interest Income\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql For the years ended December 31, 2017, 2016 and 2015, interest income totaled $0.6 million, $0.4 million\plain\cf1\f51\fs20\ql and $0.4 million, respectively.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Interest income increased by approximately $0.2 million, or 38.3%, in 2017, as compared to 2016, primarily\plain\cf1\f51\fs20\ql due to an increase in average investment balances, including money market funds classified as cash equivalents,\plain\cf1\f51\fs20\ql during 2017 resulting from our follow-on underwritten public offerings in October 2016 and October 2017. Interest\plain\cf1\f51\fs20\ql income for 2016 remained consistent with that earned during 2015.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Interest Expense\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql For both the years ended December 31, 2017 and 2016, interest expense totaled less than $0.1 million.\~\~For\plain\cf1\f51\fs20\ql the year ended December 31, 2015, interest expense totaled approximately $0.1 million.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Interest expense decreased in both 2017 and 2016, as compared to the corresponding prior period, primarily\plain\cf1\f51\fs20\ql due to a decrease in the outstanding principal amount of our note under our loan and security agreement with\plain\cf1\f51\fs20\ql Oxford Finance LLC executed on September 30, 2014.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Net Loss Applicable to Common Stockholders\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As a result of the factors discussed above, our net loss applicable to common stockholders was $66.0 million,\plain\cf1\f51\fs20\ql $38.4 million and $48.6 million for the years ended December\~31, 2017, 2016 and 2015, respectively.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Net Operating Loss Carryforwards\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In December 2017, the Tax Cuts and Jobs Act, or the TCJA, was signed into law. Among other things, the\plain\cf1\f51\fs20\ql TCJA permanently lowers the corporate federal income tax rate to 21% from the existing maximum rate of 35%,\plain\cf1\f51\fs20\ql effective for tax years including or commencing January 1, 2018. Certain provisions from the Tax Reform Act of\plain\cf1\f51\fs20\ql 1986 were not impacted by TCJA, such as those limiting the amount of net operating loss carryforwards, or NOLs,\plain\cf1\f51\fs20\ql and tax credit carryforwards that companies may utilize in any one year in the event of cumulative changes in\plain\cf1\f51\fs20\ql ownership over a three-year period in excess of 50%.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have completed several financings since the effective date of the Tax Reform Act of 1986, which as of\plain\cf1\f51\fs20\ql December\~31, 2017, have resulted in ownership changes in excess of 50% that will significantly limit our ability to\plain\cf1\f51\fs20\ql utilize our NOL and tax credit carryforwards. In December, 2017, we completed a study which determined that a\plain\cf1\f51\fs20\ql cumulative three-year ownership change in excess of 50% had occurred in February 2015. The 2017 and 2016\plain\cf1\f51\fs20\ql federal and state NOLs, tax credit carryforwards and related deferred tax assets included in Note 12 to the financial\plain\cf1\f51\fs20\ql statements appearing elsewhere in this Annual Report on Form 10-K have been adjusted to reflect the ownership\plain\cf1\f51\fs20\ql change limitations that resulted from this study.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi792\cf1\f51\fs20\ql After adjusting our federal and state NOLs to reflect the ownership change limitations that resulted from\plain\cf1\f51\fs20\ql this study, as of December\~31, 2017, we had cumulative federal and state NOLs of approximately $200.4 million\plain\cf1\f51\fs20\ql and $177.0 million available to reduce federal and state taxable income, respectively. These NOLs expire through\plain\cf1\f51\fs20\ql 2037. In addition, at December\~31, 2017, we had cumulative federal and state tax credit carryforwards of $12.7\plain\cf1\f51\fs20\ql million and $1.8 million available to reduce federal and state income taxes which expire through 2037 and 2032,\plain\cf1\f51\fs20\ql respectively. Additional ownership change limitations may result from ownership changes that occur after February\plain\cf1\f51\fs20\ql 2015.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 74\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf11\f51\fs24\b\ql Liquidity and Capital Resources\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Sources of Liquidity\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We require cash to fund our operating expenses and to make capital expenditures. Historically, we have\plain\cf1\f51\fs20\ql funded our cash requirements primarily through the following:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql sale of common stock, preferred stock and warrants;\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh270\row}}}\pard\plain\li792\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql exercise of warrants;\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql debt financing, including capital leases;\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql license fees, research funding and milestone payments under collaborative and license agreements; and\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql interest income.\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh248\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We filed a shelf registration statement on Form S-3 on August 10, 2017, which was declared effective on\plain\cf1\f51\fs20\ql September 8, 2017. Under this registration statement, we may sell, in one or more transactions, up to $250.0 million\plain\cf1\f51\fs20\ql of common stock, preferred stock, depository shares and warrants. As of February 15, 2018, we may sell up to an\plain\cf1\f51\fs20\ql additional $192.5 million of securities under this registration statement.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql See Note 9 to the financial statements appearing elsewhere in this Annual Report on Form 10-K{\*\bkmkstart _cp_text_4_662_12112272}{\*\bkmkend _cp_text_4_662_12112272}\plain\cf1\f51\fs20\ql for\plain\cf1\f51\fs20\ql additional information regarding our recent equity financings and common stock warrant activity.\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\i\ql Cash Flows\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql The following table presents a summary of the primary sources and uses of cash for the years ended\plain\cf1\f51\fs20\ql December 31, 2017, 2016 and 2015:\par\pard\plain\fi550\cf1\f51\fs20\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Year Ended December 31,\cell{
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\pard\plain\intbl\cf1\f51\fs16\b\ql (in thousands)\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2015\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Net cash provided by (used in):\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Operating activities\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr (55,259)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr (28,203)\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr (42,986)\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Investing activities\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 28,064\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 31,366\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr (33,414)\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Financing activities\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 59,157\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 50,918\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 83,015\cell{
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\pard\plain\intbl\li264\cf1\f51\fs20\b\ql Increase (decrease) in cash and cash equivalents\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\b\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\b\qr 31,962\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\b\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\b\qr 54,081\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\b\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\b\qr 6,615\cell{
{\trowd\clshdng100\clcfpat25\clcbpat25\cellx5050\clshdng100\clcfpat25\clcbpat25\cellx5335\clbrdrb\brdrdb\brdrcf1\clshdng100\clcfpat25\clcbpat25\cellx5547\clbrdrb\brdrdb\brdrcf1\clshdng100\clcfpat25\clcbpat25\cellx6571\clshdng100\clcfpat25\clcbpat25\cellx6878\clbrdrb\brdrdb\brdrcf1\clshdng100\clcfpat25\clcbpat25\cellx7092\clbrdrb\brdrdb\brdrcf1\clshdng100\clcfpat25\clcbpat25\cellx8126\clshdng100\clcfpat25\clcbpat25\cellx8433\clbrdrb\brdrdb\brdrcf1\clshdng100\clcfpat25\clcbpat25\cellx8647\clbrdrb\brdrdb\brdrcf1\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Operating Activities\plain\cf1\f51\fs20\ql .\~\~The use of cash in all periods resulted primarily from our net losses adjusted for\plain\cf1\f51\fs20\ql non-cash charges and changes in components of working capital. The increase in cash used in operating activities\plain\cf1\f51\fs20\ql for the year ended December 31, 2017, as compared to 2016, was primarily due to increased internal and external\plain\cf1\f51\fs20\ql research and development expenses as we continued to progress our IMO-2125 development program and TLR\plain\cf1\f51\fs20\ql Modulation Technology Platform. The decrease in cash used in operating activities for the year ended December 31,\plain\cf1\f51\fs20\ql 2016, as compared to 2015, was primarily due to an upfront cash payment of $15 million received in 2016 in\plain\cf1\f51\fs20\ql connection with the Vivelix Agreement; partially offset by an increase in internal and external research and\plain\cf1\f51\fs20\ql development expenses.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Investing Activities\plain\cf1\f51\fs20\ql .\~\~Cash provided by (used in) investing activities primarily consisted of the following\plain\cf1\f51\fs20\ql amounts relating to our investments in available-for-sale securities and purchases of property and equipment:\par\pard\plain\fi550\cf1\f51\fs20\ql \~
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql for the year ended December 31, 2017, the purchase of $0.2 million of property and\plain\intbl\cf1\f51\fs20\ql equipment, offset by proceeds from the maturity of available-for-sale securities of $28.3\plain\intbl\sa132\cf1\f51\fs20\ql million.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1125
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql for the year ended December 31, 2016, the purchase of $2.9 million of available-for-sale\plain\intbl\cf1\f51\fs20\ql securities and $0.4 million of property and equipment, offset by proceeds from the\plain\intbl\cf1\f51\fs20\ql maturity of available-for-sale securities of $32.7 million and proceeds from the sale of\plain\intbl\sa132\cf1\f51\fs20\ql available-for-sale securities of $2.0 million.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1125\row}}}\pard\plain\sb528\cf1\f51\fs20\qc 75\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh990
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql for the year ended December 31, 2015, the purchase of $63.1 million of available-for-sale\plain\intbl\cf1\f51\fs20\ql securities and $0.7 million of property and equipment, offset by proceeds from the\plain\intbl\cf1\f51\fs20\ql maturity of available-for-sale securities of $29.4 million and proceeds from the sale of\plain\intbl\cf1\f51\fs20\ql available-for-sale securities of $1.0 million.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh990\row}}}\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\i\ql Financing Activities\plain\cf1\f51\fs20\ql .\~\~Cash provided by financing activities primarily consisted of the following amounts\plain\cf1\f51\fs20\ql raised in connection with issuances of equity instruments:\par\pard\plain\fi550\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql for the year ended December 31, 2017, net proceeds of $53.8 million from our follow-on underwritten\plain\intbl\cf1\f51\fs20\ql public offering of our common stock in October 2017, excluding less than $0.1 million of costs that were\plain\intbl\cf1\f51\fs20\ql unpaid at December 31, 2017, and $5.7 million in aggregate net proceeds from employee stock purchases\plain\intbl\cf1\f51\fs20\ql under our 2017 Employee Stock Purchase Plan, or 2017 ESPP, and the exercise of common stock\plain\intbl\sa132\cf1\f51\fs20\ql options and warrants.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql for the year ended December 31, 2016, net proceeds of $49.0 million from our follow-on underwritten\plain\intbl\cf1\f51\fs20\ql public offering of our common stock in October 2016, excluding the $0.2 million of costs that were\plain\intbl\cf1\f51\fs20\ql unpaid at December 31, 2016, and $2.2 million in aggregate net proceeds from employee stock purchases\plain\intbl\cf1\f51\fs20\ql under our 1995 Employee Stock Purchase Plan, or 1995 ESPP, and the exercise of common stock\plain\intbl\sa132\cf1\f51\fs20\ql warrants.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1395\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh878
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql for the year ended December 31, 2015, net proceeds of $80.6 million from our follow-on underwritten\plain\intbl\cf1\f51\fs20\ql public offering of our common stock in February 2015 and $2.5 million in aggregate net proceeds from\plain\intbl\sa132\cf1\f51\fs20\ql employee stock purchases under our 1995 ESPP and the exercise of common stock options and warrants.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh878\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Financial Condition and Funding Requirements\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We have incurred operating losses in all fiscal years since our inception except 2002, 2008 and 2009, and we\plain\cf1\f51\fs20\ql had an accumulated deficit of $604.5 million at December\~31, 2017. We expect to incur substantial operating losses\plain\cf1\f51\fs20\ql in future periods. These losses, among other things, have had and will continue to have an adverse effect on our\plain\cf1\f51\fs20\ql stockholders\u8217? equity, total assets and working capital. We have received no revenues to date from the sale of\plain\cf1\f51\fs20\ql commercial products. As of February 15, 2018, substantially all of our revenues have been from collaboration and\plain\cf1\f51\fs20\ql license agreements. We have devoted substantially all of our efforts to research and development, including clinical\plain\cf1\f51\fs20\ql trials, and we have not completed development of any commercial products. Because of the numerous risks and\plain\cf1\f51\fs20\ql uncertainties associated with developing commercial products, we are unable to predict the extent of any future\plain\cf1\f51\fs20\ql losses, whether or when any of our products will become commercially available or when we will become\plain\cf1\f51\fs20\ql profitable, if at all.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We do not expect to generate significant additional funds internally until we successfully complete\plain\cf1\f51\fs20\ql development and obtain marketing approval for products, either alone or in collaboration with third parties, which\plain\cf1\f51\fs20\ql we expect will take a number of years. In addition, we have no committed external sources of funds.\par\pard\plain\fi792\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We had cash, cash equivalents and investments of approximately $112.6 million at December\~31, 2017. We\plain\cf1\f51\fs20\ql believe that, based on our current operating plan, our existing cash, cash equivalents and investments will enable us\plain\cf1\f51\fs20\ql to fund our operations into the second quarter of 2019. Specifically, we believe that our available funds will be\plain\sa132\cf1\f51\fs20\ql sufficient to enable us to:
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql complete the dose-finding portion of our ongoing Phase 1/2 clinical trial of IMO-2125 in\plain\intbl\cf1\f51\fs20\ql combination with pembrolizumab in anti-PD1 refractory metastatic melanoma and complete\plain\intbl\sa132\cf1\f51\fs20\ql enrollment in the Phase 2 portion of this trial in combination with ipilimumab;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql initiate a Phase 3 clinical trial of IMO-2125 in combination with ipilimumab for the treatment of\plain\intbl\sa132\cf1\f51\fs20\ql anti-PD1 refractory metastatic melanoma;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql continue to enroll patients in our Phase 1b intra-tumoral monotherapy clinical trial of\plain\intbl\sa132\cf1\f51\fs20\ql IMO-2125 in multiple refractory tumor types; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh652\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql complete our ongoing Phase 2 clinical trial of IMO-8400 in patients with dermatomyositis.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh270\row}}}\pard\plain\li990\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql We expect that we will need to raise additional funds in order to complete these trials, conduct any other\plain\cf1\f51\fs20\ql clinical development of our TLR drug candidates or to conduct any other development of our nucleic acid chemistry\par\pard\plain\sb528\cf1\f51\fs20\qc 76\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\cf1\f51\fs20\ql technology, and to fund our operations. We are seeking and expect to continue to seek additional funding through\plain\cf1\f51\fs20\ql collaborations, the sale or license of assets or financings of equity or debt securities. We believe that the key factors\plain\cf1\f51\fs20\ql that will affect our ability to obtain funding are:
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa132\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the results of our clinical and preclinical development activities in our rare disease program, our\plain\intbl\cf1\f51\fs20\ql immuno-oncology program and our nucleic acid chemistry research program, and our ability to advance\plain\intbl\sa132\cf1\f51\fs20\ql our drug candidates and nucleic acid chemistry technology on the timelines anticipated;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh900\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f51\fs20\ql the cost, timing, and outcome of regulatory reviews;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh518\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1012
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql competitive and potentially competitive products and technologies and investors' receptivity to\plain\intbl\cf1\f51\fs20\ql our drug candidates and the technology underlying them in light of competitive products and\plain\intbl\sa110\cf1\f51\fs20\ql technologies;\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh1012\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh765
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa110\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the receptivity of the capital markets to financings by biotechnology companies generally and companies\plain\intbl\sa110\cf1\f51\fs20\ql with drug candidates and technologies such as ours specifically; and\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh765\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh922
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\sa264\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql our ability to enter into additional collaborations with biotechnology and pharmaceutical companies and\plain\intbl\sa264\cf1\f51\fs20\ql the success of such collaborations.\cell{
{\trowd\clvertalc\cellx540\cellx880\clvertalc\cellx900\cellx9688\trrh922\row}}}\pard\plain\fi594\cf1\f51\fs20\ql In addition, increases in expenses or delays in clinical development may adversely impact our cash position\plain\cf1\f51\fs20\ql and require additional funds or cost reductions.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Financing may not be available to us when we need it or may not be available to us on favorable or\plain\cf1\f51\fs20\ql acceptable terms or at all. We could be required to seek funds through collaborative alliances or through other\plain\cf1\f51\fs20\ql means that may require us to relinquish rights to some of our technologies, drug candidates or drugs that we would\plain\cf1\f51\fs20\ql otherwise pursue on our own. In addition, if we raise additional funds by issuing equity securities, our then existing\plain\cf1\f51\fs20\ql stockholders will experience dilution. The terms of any financing may adversely affect the holdings or the rights of\plain\cf1\f51\fs20\ql existing stockholders. An equity financing that involves existing stockholders may cause a concentration of\plain\cf1\f51\fs20\ql ownership. Debt financing, if available, may involve agreements that include covenants limiting or restricting our\plain\cf1\f51\fs20\ql ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends,\plain\cf1\f51\fs20\ql and are likely to include rights that are senior to the holders of our common stock. Any additional debt or equity\plain\cf1\f51\fs20\ql financing may contain terms which are not favorable to us or to our stockholders, such as liquidation and other\plain\cf1\f51\fs20\ql preferences, or liens or other restrictions on our assets. As discussed in Note 12 to the financial statements\plain\cf1\f51\fs20\ql appearing elsewhere in this Annual Report on Form 10-K, additional equity financings may also result in\plain\cf1\f51\fs20\ql cumulative changes in ownership over a three-year period in excess of 50% which would limit the amount of net\plain\cf1\f51\fs20\ql operating loss and tax credit carryforwards that we may utilize in any one year.\par\pard\plain\fi594\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql If we are unable to obtain adequate funding on a timely basis or at all, we will be required to terminate,\plain\cf1\f51\fs20\ql modify or delay preclinical or clinical trials of one or more of our drug candidates, significantly curtail or terminate\plain\cf1\f51\fs20\ql discovery or development programs for new drug candidates or relinquish rights to portions of our technology, drug\plain\cf1\f51\fs20\ql candidates and/or products.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Contractual Obligations\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of December\~31, 2017, our contractual commitments and the effects such commitments are expected to\plain\cf1\f51\fs20\ql have on our liquidity and cash flows in future periods are as follows:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\trqc\clvertalb\cellx1918\clvertalb\cellx2058\clvertalb\cellx2280\clvertalb\cellx2841\clvertalb\cellx2981\clvertalb\cellx3181\clvertalb\cellx3742\clvertalb\cellx3882\clvertalb\cellx4081\clvertalb\cellx4865\clvertalb\cellx5005\clvertalb\cellx5205\clvertalb\cellx5989\clvertalb\cellx6129\clvertalb\cellx6329\clvertalb\cellx7113\clvertalb\cellx7253\clvertalb\cellx7453\clvertalb\cellx8237\clvertalb\cellx8377\clvertalb\cellx8759\clvertalb\cellx9543\clvertalb\cellx9688\trrh66
\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1918\clvertalb\cellx2058\clvertalb\cellx2280\clvertalb\cellx2841\clvertalb\cellx2981\clvertalb\cellx3181\clvertalb\cellx3742\clvertalb\cellx3882\clvertalb\cellx4081\clvertalb\cellx4865\clvertalb\cellx5005\clvertalb\cellx5205\clvertalb\cellx5989\clvertalb\cellx6129\clvertalb\cellx6329\clvertalb\cellx7113\clvertalb\cellx7253\clvertalb\cellx7453\clvertalb\cellx8237\clvertalb\cellx8377\clvertalb\cellx8759\clvertalb\cellx9543\clvertalb\cellx9688\trrh66\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1918\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2058\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9547\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198
\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Payments\~Due\~by\~Period\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1918\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2058\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9547\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh198\row}}}
{\trowd\trqc\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1918\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2058\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2842\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2982\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3743\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3883\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4867\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5007\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5991\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6131\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7115\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7255\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8239\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8379\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9545\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh396
\pard\plain\intbl\cf1\f51\fs16\b\ql (in thousands)\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Total\cell\pard\plain\intbl\cf1\f51\fs16\qc \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2018\cell\pard\plain\intbl\cf1\f51\fs16\qc \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2019\cell\pard\plain\intbl\cf1\f51\fs16\qc \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2020\cell\pard\plain\intbl\cf1\f51\fs16\qc \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2021\cell\pard\plain\intbl\cf1\f51\fs16\qc \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2022\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc 2023 and\plain\intbl\cf1\f51\fs16\b\qc thereafter\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell{
{\trowd\trqc\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1918\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2058\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2842\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2982\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3743\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3883\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4867\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5007\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5991\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6131\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7115\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7255\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8239\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8379\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9545\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh396\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1918\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2058\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2841\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2981\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3181\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3742\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3882\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4081\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4865\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5005\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5205\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5989\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6129\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6329\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7113\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7253\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7453\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8237\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8377\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8759\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql Operating leases\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 9,458\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2,024\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2,084\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2,018\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1,984\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1,348\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1918\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2058\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2280\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2841\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2981\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3181\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3742\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3882\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4081\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4865\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5005\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5205\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5989\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6129\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6329\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7113\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7253\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7453\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8237\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8377\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8759\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx1918\clvertalb\cellx2058\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2841\clvertalb\cellx2981\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3181\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3742\clvertalb\cellx3882\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4081\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4865\clvertalb\cellx5005\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5205\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5989\clvertalb\cellx6129\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6329\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7113\clvertalb\cellx7253\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7453\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8237\clvertalb\cellx8377\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8759\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9543\clvertalb\cellx9688\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql Loan and security\plain\intbl\cf1\f51\fs20\ql agreement\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 209\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 209\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1918\clvertalb\cellx2058\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2280\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2841\clvertalb\cellx2981\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3181\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3742\clvertalb\cellx3882\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4081\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4865\clvertalb\cellx5005\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5205\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5989\clvertalb\cellx6129\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6329\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7113\clvertalb\cellx7253\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7453\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8237\clvertalb\cellx8377\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8759\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9543\clvertalb\cellx9688\trrh495\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1918\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2058\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2280\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2841\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2981\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3181\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3742\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3882\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4081\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4865\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5005\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5205\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5989\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6129\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6329\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7113\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7253\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7453\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8237\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8377\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8759\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql Total\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 9,667\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2,233\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2,084\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 2,018\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1,984\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr 1,348\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\ri66\cf1\f51\fs20\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1918\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2058\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2280\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2841\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2981\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3181\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3742\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3882\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4081\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4865\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5005\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5205\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5989\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6129\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6329\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7113\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7253\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7453\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8237\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8377\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8759\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9543\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh248\row}}}\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql Our only material lease commitments relate to our facilities in Cambridge, Massachusetts, which expires on\plain\cf1\f51\fs20\ql August\~31, 2022 subject to a five-year renewal option exercisable by us, and Exton, Pennsylvania, which expires on\plain\cf1\f51\fs20\ql May 31, 2020 subject to a three-year renewal option exercisable by us.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql See Note 7 to the financial statements appearing elsewhere in this Annual Report on Form 10-K for\plain\cf1\f51\fs20\ql additional information regarding our note payable.\par\pard\plain\sb528\cf1\f51\fs20\qc 77\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql In the normal course of business, we enter into contracts with clinical research organizations, drug\plain\cf1\f51\fs20\ql manufacturers and other vendors\~\~for preclinical and clinical research studies, research and development supplies and\plain\cf1\f51\fs20\ql other services and products for operating purposes. These contracts generally provide for termination on notice, and\plain\cf1\f51\fs20\ql therefore are cancellable contracts and not included in the table of contractual obligations and commitments.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql Off-Balance Sheet Arrangements\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql As of December\~31, 2017, we had no off-balance sheet arrangements.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\i\ql New Accounting Pronouncements\par\pard\plain\li264\cf1\f51\fs20\ql \~\par\pard\plain\fi594\cf1\f51\fs20\ql New accounting pronouncements are discussed in Note 2 in the Notes to the Financial Statements in this\plain\cf1\f51\fs20\ql Annual Report on Form10-K.\par\pard\plain\sb528\cf1\f51\fs20\qc 78\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}{\*\bkmkstart item_1_3_10}{\*\bkmkend item_1_3_10}\par\pard\plain\li1342\fi-1342\cf11\f51\fs24\b\ql Item\~7A.Quantitative and Qualitative Disclosures about Market Risk.\plain\li1342\cf12\f51\fs24\b\ql \~{\*\bkmkstart item7aquantitativeandqualitative}{\*\bkmkend item7aquantitativeandqualitative}\par\pard\plain\li1342\fi-1342\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\qj As of December 31, 2017, all material assets and liabilities are in U.S.\~dollars, which is our functional\plain\cf1\f51\fs20\qj currency.\par\pard\plain\fi550\cf1\f51\fs20\qj \~\par\pard\plain\fi550\cf1\f51\fs20\ql We maintain investments in accordance with our investment policy. The primary objectives of our investment\plain\cf1\f51\fs20\ql activities are to preserve principal, maintain proper liquidity to meet operating needs and maximize yields. Although\plain\cf1\f51\fs20\ql our investments are subject to credit risk, our investment policy specifies credit quality standards for our\plain\cf1\f51\fs20\ql investments and limits the amount of credit exposure from any single issue, issuer or type of investment. We\plain\cf1\f51\fs20\ql regularly review our investment holdings in light of the then current economic environment. At December 31, 2017,\plain\cf1\f51\fs20\ql all of our invested funds were invested in a money market fund classified in cash and cash equivalents on the\plain\cf1\f51\fs20\ql accompanying balance sheet.\par\pard\plain\fi550\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Based on a hypothetical ten percent adverse movement in interest rates, the potential losses in future earnings,\plain\cf1\f51\fs20\ql fair value of risk sensitive financial instruments, and cash flows are immaterial, although the actual effects may\plain\cf1\f51\fs20\ql differ materially from the hypothetical analysis.\par\pard\plain\sb528\cf1\f51\fs20\qc 79\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}{\*\bkmkstart item_1_3_11}{\*\bkmkend item_1_3_11}\par\pard\plain\li1210\fi-1210\cf11\f51\fs24\b\ql Item\~8.Financial Statements and Supplementary Data.\plain\li1210\cf12\f51\fs24\b\ql \~{\*\bkmkstart item8financialstatementsandsuppl}{\*\bkmkend item8financialstatementsandsuppl}\par\pard\plain\li1210\fi-1210\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql All financial statements required to be filed hereunder are filed as listed under Item\~15(a) of this Annual\plain\cf1\f51\fs20\ql Report on Form\~10-K and are incorporated herein by this reference.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Quarterly Operating Results (Unaudited)\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql The following table presents the unaudited statement of operations and comprehensive loss data for each of\plain\cf1\f51\fs20\ql the eight quarters in the period ended December\~31, 2017. The information for each of these quarters is unaudited,\plain\cf1\f51\fs20\ql but has been prepared on the same basis as the audited financial statements appearing elsewhere in this Annual\plain\cf1\f51\fs20\ql Report on Form\~10-K. In our opinion, all necessary adjustments, consisting only of normal recurring adjustments,\plain\cf1\f51\fs20\ql have been made to present fairly the unaudited quarterly results when read in conjunction with the audited financial\plain\cf1\f51\fs20\ql statements and the notes thereto appearing elsewhere in this document. These operating results are not necessarily\plain\cf1\f51\fs20\ql indicative of the results of operations that may be expected for any future period.\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh66
\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell\pard\plain\intbl\cf1\f51\fs1\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Three months ended\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1233\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9572\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh167\row}}}
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\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Dec.\~31,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Sep.\~30,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Jun.\~30,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Mar.\~31,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Dec.\~31,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Sep.\~30,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Jun.\~30,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc Mar.\~31,\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell{
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{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1233\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2272\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3308\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3520\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4356\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4568\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5415\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5627\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6431\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6643\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7467\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7679\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8507\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8719\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9566\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh167
\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2017\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc 2016\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1233\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2272\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3308\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx3520\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4356\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx4568\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5415\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5627\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6431\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6643\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7467\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7679\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8507\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8719\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9566\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh167\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1233\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1445\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9572\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh167
\pard\plain\intbl\cf1\f51\fs13\qc \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\b\qc (In thousands, except per share data)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1233\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx1445\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9572\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx9688\trrh167\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh666
\pard\plain\intbl\cf1\f51\fs13\b\ql Statement of\plain\intbl\cf1\f51\fs13\b\ql Operations and\plain\intbl\cf1\f51\fs13\b\ql Comprehensive\plain\intbl\cf1\f51\fs13\b\ql (Loss) Income Data:\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\~\~\~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh666\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql Alliance revenue\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 173\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 164\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 187\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 378\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 15,281\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 323\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 301\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 294\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql Operating expenses:\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh333
\pard\plain\intbl\li132\cf1\f51\fs13\ql Research and\plain\intbl\li132\cf1\f51\fs13\ql development\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 10,365\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 10,912\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 17,891\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 11,485\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 11,007\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 9,393\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 10,128\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 9,296\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh333\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh333
\pard\plain\intbl\li132\cf1\f51\fs13\ql General and\plain\intbl\li132\cf1\f51\fs13\ql administrative\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 4,828\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 3,919\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 3,888\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 4,081\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 3,531\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 3,907\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 3,778\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 3,916\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh333\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh333
\pard\plain\intbl\li264\cf1\f51\fs13\ql Total operating\plain\intbl\li264\cf1\f51\fs13\ql expenses\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 15,193\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 14,831\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 21,779\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 15,566\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 14,538\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 13,300\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 13,906\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 13,212\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh333\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh333
\pard\plain\intbl\cf1\f51\fs13\ql (Loss) income from\plain\intbl\cf1\f51\fs13\ql operations\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (15,020)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,667)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (21,592)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (15,188)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 743\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,977)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (13,605)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,918)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh333\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh333
\pard\plain\intbl\cf1\f51\fs13\ql Other income\plain\intbl\cf1\f51\fs13\ql (expense):\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh333\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187
\pard\plain\intbl\li132\cf1\f51\fs13\ql Interest income\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 118\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 159\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 144\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 153\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 95\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 90\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 110\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 120\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\li132\cf1\f51\fs13\ql Interest expense\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (11)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (13)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (16)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (17)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (19)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (21)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (23)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh500
\pard\plain\intbl\li132\cf1\f51\fs13\ql Foreign currency\plain\intbl\li132\cf1\f51\fs13\ql exchange gain\plain\intbl\li132\cf1\f51\fs13\ql (loss)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (14)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (11)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (6)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr \~1\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr \~3\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 31\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (2)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh500\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql Net (loss) income\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,926)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,530)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (21,471)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (15,057)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 822\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,903)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (13,485)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,823)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh666
\pard\plain\intbl\cf1\f51\fs13\ql Net (loss) income per\plain\intbl\cf1\f51\fs13\ql share applicable to\plain\intbl\cf1\f51\fs13\ql common stockholders\plain\intbl\cf1\f51\fs13\ql (1)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh666\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187
\pard\plain\intbl\li132\cf1\f51\fs13\ql \u8212? Basic\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.08)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.14)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 0.01\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.11)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.11)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\li132\cf1\f51\fs13\ql \u8212? Diluted\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.08)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.14)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 0.01\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.10)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.11)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (0.11)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh1332
\pard\plain\intbl\cf1\f51\fs13\ql Weighted-average\plain\intbl\cf1\f51\fs13\ql number of common\plain\intbl\cf1\f51\fs13\ql shares used in\plain\intbl\cf1\f51\fs13\ql computing net (loss)\plain\intbl\cf1\f51\fs13\ql income per share\plain\intbl\cf1\f51\fs13\ql applicable to\plain\intbl\cf1\f51\fs13\ql common stockholders\plain\intbl\cf1\f51\fs13\ql (1) (2)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh1332\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\li132\cf1\f51\fs13\ql \u8212? Basic\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 181,176\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 149,638\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 149,412\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 149,100\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 146,255\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 121,389\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 121,323\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 121,284\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187
\pard\plain\intbl\li132\cf1\f51\fs13\ql \u8212? Diluted\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 181,176\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 149,638\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 149,412\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 149,100\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 151,930\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 121,389\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 121,323\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 121,284\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql Comprehensive loss:\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187
\pard\plain\intbl\cf1\f51\fs13\ql Net (loss) income\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,926)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,530)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (21,471)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (15,057)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 822\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,903)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (13,485)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,823)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clvertalb\cellx1718\clvertalb\cellx2272\clvertalb\cellx2484\clvertalb\cellx2753\clvertalb\cellx3307\clvertalb\cellx3519\clvertalb\cellx3792\clvertalb\cellx4354\clvertalb\cellx4566\clvertalb\cellx4859\clvertalb\cellx5413\clvertalb\cellx5625\clvertalb\cellx5898\clvertalb\cellx6429\clvertalb\cellx6641\clvertalb\cellx6910\clvertalb\cellx7464\clvertalb\cellx7676\clvertalb\cellx7949\clvertalb\cellx8503\clvertalb\cellx8715\clvertalb\cellx9008\clvertalb\cellx9562\clvertalb\cellx9688\trrh187\row}}}
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh333
\pard\plain\intbl\cf1\f51\fs13\ql Other comprehensive\plain\intbl\cf1\f51\fs13\ql income (loss):\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1233\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1445\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx1718\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2272\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2484\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx2753\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3307\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3519\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx3792\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4354\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4566\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx4859\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5413\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5625\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx5898\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6429\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6641\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx6910\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7464\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7676\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx7949\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8503\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx8715\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9008\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9562\clvertalb\clshdng100\clcfpat25\clcbpat25\cellx9688\trrh333\row}}}
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh666
\pard\plain\intbl\li132\cf1\f51\fs13\ql Unrealized gain\plain\intbl\li132\cf1\f51\fs13\ql (loss) on\plain\intbl\li132\cf1\f51\fs13\ql available-for-sale\plain\intbl\li132\cf1\f51\fs13\ql securities\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr \~2\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (1)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 16\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (16)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (13)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 12\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 134\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrs\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrs\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrs\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrs\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrs\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrs\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh666\row}}}
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\pard\plain\intbl\li264\cf1\f51\fs13\ql Total other\plain\intbl\li264\cf1\f51\fs13\ql comprehensive\plain\intbl\li264\cf1\f51\fs13\ql income (loss)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr \~2\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (1)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr \~\u8212?\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 16\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (16)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\qr (13)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 12\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 134\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs13\ql Comprehensive (loss)\plain\intbl\cf1\f51\fs13\ql income\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,924)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (14,531)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (21,471)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (15,041)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\ri44\cf1\f51\fs13\qr 806\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,916)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (13,473)\cell\pard\plain\intbl\cf1\f51\fs13\ql \~\cell\pard\plain\intbl\cf1\f51\fs13\ql $\cell\pard\plain\intbl\cf1\f51\fs13\qr (12,689)\cell\pard\plain\intbl\cf1\f51\fs15\ql \~\cell{
{\trowd\trqc\clvertalb\cellx1233\clvertalb\cellx1445\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx1718\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2272\clvertalb\cellx2484\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx2753\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3307\clvertalb\cellx3519\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx3792\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4354\clvertalb\cellx4566\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx4859\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5413\clvertalb\cellx5625\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx5898\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6429\clvertalb\cellx6641\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx6910\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7464\clvertalb\cellx7676\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx7949\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx8503\clvertalb\cellx8715\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9008\clbrdrb\brdrdb\brdrcf1\clvertalb\cellx9562\clvertalb\cellx9688\trrh333\row}}}\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\par\pard\plain
{\trowd\clvertalc\cellx1\cellx380\clvertalc\cellx480\cellx9688\trrh245
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql (1)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql Computed on the basis described in Note\~15 to the financial statements appearing elsewhere in this Form 10-K.\cell{
{\trowd\clvertalc\cellx1\cellx380\clvertalc\cellx480\cellx9688\trrh245\row}}}
\par\pard\plain
{\trowd\clvertalc\cellx1\cellx380\clvertalc\cellx480\cellx9688\trrh668
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql (2)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\ql In the quarter ending December 31, 2016, shares used in computing diluted net income per share includes 1,315,000\plain\intbl\cf1\f51\fs18\ql common stock equivalents related to exercisable stock options and 4,360,000 common stock equivalents related to\plain\intbl\cf1\f51\fs18\ql exercisable warrants.\cell{
{\trowd\clvertalc\cellx1\cellx380\clvertalc\cellx480\cellx9688\trrh668\row}}}\pard\plain\li528\fi-528\cf1\f51\fs20\ql \~\par\pard\plain\sb528\cf1\f51\fs20\qc 80\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par\par\pard\plain\li220\ri220\cf1\f51\fs20\ql \~
\page\pard\plain\sa660\ul{\field{\*\fldinst HYPERLINK \\l "toc_12112272" }{\*\fldrslt\cf3\f51\fs20\ql Table of Contents}}{\*\bkmkstart item_1_3_12}{\*\bkmkend item_1_3_12}\par\pard\plain\li1210\fi-1210\cf11\f51\fs24\b\ql Item\~9.\~\~\~\~Changes in and Disagreements with Accountants on Accounting and Financial\plain\li1210\cf11\f51\fs24\b\ql Disclosure.{\*\bkmkstart item9changesinanddisagreementswi}{\*\bkmkend item9changesinanddisagreementswi}\par\pard\plain\li1210\fi-1210\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql None.\~\par\pard\plain\fi550\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_13}{\*\bkmkend item_1_3_13}\par\pard\plain\li1210\fi-1210\cf11\f51\fs24\b\ql Item\~9A.\~\~ \~\~Controls and Procedures.{\*\bkmkstart item9acontrolsandprocedures_8478}{\*\bkmkend item9acontrolsandprocedures_8478}\par\pard\plain\li1210\fi-1210\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Disclosure Controls and Procedures\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Our management, with the participation of our principal executive officer and principal financial officer,\plain\cf1\f51\fs20\ql evaluated the effectiveness of our disclosure controls and procedures (as defined in Rules\~13a-15(e) and 15d-15(e)\plain\cf1\f51\fs20\ql under the Exchange Act) as of December\~31, 2017. In designing and evaluating our disclosure controls and\plain\cf1\f51\fs20\ql procedures, management recognizes that any controls and procedures, no matter how well designed and operated,\plain\cf1\f51\fs20\ql can provide only reasonable assurance of achieving their objectives and our management necessarily applied its\plain\cf1\f51\fs20\ql judgment in evaluating the cost-benefit relationship of possible controls and procedures. Based on this evaluation,\plain\cf1\f51\fs20\ql our principal executive officer and principal financial officer concluded that as of December\~31, 2017, our disclosure\plain\cf1\f51\fs20\ql controls and procedures were (1)\~designed to ensure that material information relating to us is made known to our\plain\cf1\f51\fs20\ql principal executive officer and principal financial officer by others, particularly during the period in which this\plain\cf1\f51\fs20\ql report was prepared, and (2)\~effective, in that they provide reasonable assurance that information required to be\plain\cf1\f51\fs20\ql disclosed by us in the reports we file or submit under the Exchange Act is recorded, processed, summarized and\plain\cf1\f51\fs20\ql reported within the time periods specified in the SEC\u8217?s rules and forms.\par\pard\plain\fi528\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\b\ql Internal Control over Financial Reporting\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx1\cellx400\clvertalc\cellx440\cellx9688\trrh248
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\b\ql a)\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\b\i\ql Management\u8217?s Annual Report on Internal Control over Financial Reporting\cell{
{\trowd\clvertalc\cellx1\cellx400\clvertalc\cellx440\cellx9688\trrh248\row}}}\pard\plain\li528\fi-528\cf1\f51\fs20\ql \~\par\pard\plain\fi550\cf1\f51\fs20\ql Our management, with the participation of our principal executive officer and principal financial officer, is\plain\cf1\f51\fs20\ql responsible for establishing and maintaining adequate internal control over financial reporting. Internal control over\plain\cf1\f51\fs20\ql financial reporting is defined in Rule\~13a-15(f) and 15d-15(f) promulgated under the Exchange Act as a process\plain\cf1\f51\fs20\ql designed by, or under the supervision of, the Company\u8217?s principal executive and principal financial officers\plain\cf1\f51\fs20\ql and effected by the Company\u8217?s board of directors, management and other personnel, to provide reasonable\plain\cf1\f51\fs20\ql assurance regarding the reliability of financial reporting and the preparation of financial statements for external\plain\cf1\f51\fs20\ql purposes in accordance with generally accepted accounting principles and includes those policies and procedures\plain\cf1\f51\fs20\ql that:\par\pard\plain\fi528\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh495
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Pertain to the maintenance of records that in reasonable detail accurately and fairly reflect the transactions\plain\intbl\cf1\f51\fs20\ql and dispositions of the assets of the Company;\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh495\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh990
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\fs20\ql ·\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql Provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial\plain\intbl\cf1\f51\fs20\ql statements in accordance with generally accepted accounting principles, and that receipts and expenditures\plain\intbl\cf1\f51\fs20\ql of the Company are being made only in accordance with authorizations of management and directors of the\plain\intbl\cf1\f51\fs20\ql Company;\~and\cell{
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh990\row}}}\pard\plain\li792\fi-264\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\clvertalc\cellx480\cellx720\clvertalc\cellx721\cellx9688\trrh495
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\cf1\f53\